Serine protease inhibitors

ABSTRACT

The present invention relates to certain substituted oxadiazole, thiadiazoles and triazole peptoids which are useful as inhibitors of serine proteases. Compounds of the invention are useful for treating, for example, adult respiratory distress syndrome, septic shock, and myocardial ischemia-reperfusion injury.

[0001] This application is a continuation-in-part of U.S. Ser. No.08/760,916, filed Dec. 6, 19996, now U.S. Pat. No. 5,861,380, which is acontinuation-in-part of U.S. Ser. No. 08/345,820 filed Nov. 21, 1994,now U.S. Pat. No. 5,618,792.

[0002] The present invention relates to certain substituted oxadiazole,thiadiazole and triazole peptoids which are useful as inhibitors ofserine proteases.

BACKGROUND OF THE INVENTION

[0003] The serine proteases are a class of enzymes which includeselastase, chymotrypsin, cathepsin G, trypsin and thrombin. Theseproteases have in common a catalytic triad consisting of Serine-195,Histidine-57 and Aspartic acid-102 (chymotrypsin numbering system).Human neutrophil elastase (HNE) is a proteolytic enzyme secreted bypolymorphonuclear leukocytes (PMNs) in response to a variety ofinflammatory stimuli. This release of HNE and its extracellularproteolytic activity are highly regulated and are normal, beneficialfunctions of PMNs. The degradative capacity of HNE, under normalcircumstances, is modulated by relatively high plasma concentrations ofα₁-proteinase inhibitor (α₁-PI). However, stimulated PMNs produce aburst of active oxygen metabolites, some of which (hypochlorous acid forexample) are capable of oxidizing a critical methionine residue inα₁-PI. Oxidized α₁-PI has been shown to have limited potency as an HNEinhibitor and it has been proposed that alteration of thisprotease/antiprotease balance permits HNE to perform its degradativefunctions in localized and controlled environments.

[0004] Despite this balance of protease/antiprotease activity, there areseveral human disease states in which a breakdown of this controlmechanism is implicated in the pathogenesis of the condition. Impropermodulation of HNE activity has been suggested as a contributing factorin adult respiratory distress syndrome, septic shock and multiple organfailure. A series of studies also have indicated the involvement of PMNsand neutrophil elastase in myocardial ischemia-reperfusion injury.Humans with below-normal levels of α₁-PI have an increased probabilityof developing emphysema. HNE-mediated processes are implicated in otherconditions such as arthritis, periodontal disease, glomerulonephritis,dermatitis psoriasis, cystic fibrosis, chronic bronchitis,atherosclerosis, Alzheimer's disease, organ transplantation, cornealulcers, and invasion behavior of malignant tumors.

[0005] There is a need for effective inhibitors of HNE as therapeuticand as prophylactic agents for the treatment and/or prevention ofelastase-mediated problems.

SUMMARY OF THE INVENTION

[0006] The present invention provides compounds which are useful asserine protease inhibitors, including human neutrophil elastase. Thesecompounds are characterized by their relatively low molecular weight,high potency and selectivity with respect to HNE. Additionally, certaincompounds of the invention have demonstrated oral bioavailability asexhibited by their higher blood levels after oral dosing. Oralbioavailability allows oral dosing for use in chronic disease, with theadvantages of self-administration and decreased cost over other means ofadministration. The compounds described herein can be used effectivelyto prevent, alleviate or otherwise treat disease states characterized bythe degradation of connective tissue by proteases in humans.

[0007] The present invention provides compounds comprising oxadiazole,thiadiazole or triazole ring structures, and can be genericallydescribed by the formula:

[0008] wherein Z is a serine protease binding moiety, preferably anelastase binding moiety, and most preferably a human neutrophil elastasebinding moiety. Specifically, Z is a carbonyl containing group,preferably an α-amino carbonyl containing group where the carbonylcarbon is covalently attached to the carbon of the heterocycle.

[0009] R₁ is alkyl, alkenyl or alkynyl optionally substituted with 1 ormore, preferably 1-3, halo, hydroxyl, cyano, nitro, haloalkyl,alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide or —O—(C₅-C₆)aryl; hydroxyl, amino,alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl,(C₅-C₁₂)aryl, (C₅-C₁₂)arylalkyl, (C₅-C₁₂)arylalkenyl, fused(C₅-C₁₂)aryl-cycloalkyl or alkyl fused (C₅-C₁₂)aryl-cycolalkyloptionally comprising 1-4 heteroatoms selected from N, O and S, andoptionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl,amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,(C₅-C6)aryl, —O—(C₅-C₆)aryl, arylcarboxamide, alkylthio orhaloalkylthio.

[0010] X and Y are independently O, S or N, wherein N is optionallysubstituted with alkyl or alkenyl optionally substituted with 1-3 haloatoms; (C₅-C₆)aryl, arylalkyl or arylalkenyl optionally comprising 1-3heteroatoms selected from N, O and S, and optionally substituted withhalo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio. Preferably, at least one of X or Y is N. It will beunderstood that where X or Y is a substituted N, both X and Y are N.Preferably, the compounds of the present invention comprise1,2,4-oxadiazole (i.e., X is O; Y is N) or 1,3,4 oxadiazole rings (i.e.,X is N; Y is O).

[0011] The compounds of the present invention may be convenientlycategorized as Groups I through VI.

[0012] In one preferred embodiment, the invention provides compounds ofthe formula (Group 1):

[0013] wherein X, Y and R, are described above;

[0014] R₂ and R₃ are independently or together H; alkyl or alkenyloptionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino,alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl,guanidinyl, or amidylguanidine; —RCOR′, —RCOOR′, —RNR′R″R° or—RC(O)NR′R″ where R is alkyl or alkenyl, and R′,R″ and R° areindependently H, alkyl, alkenyl, cycloalkyl or (C₅-C₆)aryl; orcycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl,alkyl-thioaryl, alkyl-aminoaryl, (C₅-C₁₂)aryl, (C₅-C₁₂)arylalkyl or(C₅-C₁₂)arylalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S, and optionally substituted with halo, cyano, keto, nitro,hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,(C₅-C₆)aryl, —O—(C₅-C₆)aryl, arylcarboxamide, alkylthio orhaloalkylthio;

[0015] A is a direct bond, —C(O)—, —NH—C(O)—, —S(O)₂—, —NH—S(O)₂—,—OC(O)—, —C— or an amino acid selected from, but not limited to,proline, isoleucine, cyclohexylalanine, cysteine optionally substitutedat the sulfur with alkyl, alkenyl or phenyl optionally substituted withhalo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,arylcarboxamide, alkylthio or haloalkylthio; phenylalanine,homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid;tetrahydrosioquinoline-2-carboxylic acid optionally substituted withalkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro,haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio; tryptophan, tyrosine, serine or threonine optionallysubstituted with alkyl or aryl; histidine, methionine, valine,norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine,glutamine, ornithine and lysine optionally substituted at the side chainnitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl,alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkylor aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkylor alkyl fused aryl-cycloalkyl optionally comprising 1 or moreheteroatoms selected from N, O and S; and

[0016] R₄ is H, alkyl, alkenyl or alkynyl; or cycloalkyl,alkylcycloalkyl, (C₅-C₁₂)aryl, (C₅-C₁₂)arylalkyl, fused(C₅-C₁₂)aryl-cycloalkyl or fused alkyl (C₅-C₁₂)aryl-cycloalkyloptionally comprising one or more heteroatoms selected from N, O and S,and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano,nitro, hydroxyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino,carboxyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl,arylcarboxamido, alkylthio or haloalkylthio or is absent.

[0017] In a preferred embodiment, X is N and Y is O. In anotherpreferred embodiment, X is O and Y is N. Preferably, R₄—A is anarylalkyloxycarbonyl such as benzyloxycarbonyl; alkoxycarbonyl,arylsulfonyl, alkylsulfonyl or alkyl.

[0018] Preferably, R₂ and R₃ are alkyl such as methyl or isopropyl, orH. In one preferred embodiment, R₂ is isopropyl and R₃ is H.

[0019] In a preferred embodiment of the invention, R₁ is an optionallysubstituted aryl or arylalkyl group, such as an α,α-dimethylbenzyl,benzyl or phenyl group. According to several preferred embodiments, thebenzene ring is substituted with an alkyl, such as methyl; with ahaloalkyl, such as trifluoromethyl; or with a dialkylamino, preferablydimethylamino. In yet another embodiment, R₁ is a fused arylalkyl groupsuch as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment,R₁ is an alkyl group, preferably (C₁-C₈)alkyl, either straight chain orbranched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,t-butyl, etc.

[0020] The present invention further provides compounds of the formula(Group II):

[0021] wherein

[0022] X, Y, R₁, R₂ and R₃ are as described above;

[0023] B is —S(O)₂—, —C(O)—, —OC(O)— or —CH₂C(O)—;

[0024] R′₂ and R′₃ are independently or together H; alkyl or alkenyloptionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino,alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl,guanidinyl, or amidylguanidine; —RCOR′, —RCOOR′, —RNR′R″R° or—RC(O)NR′R″ where R is alkyl or alkenyl, and R′, R″ and R° areindependently H, alkyl, alkenyl, cycloalkyl or(C₅-C₆)aryl; orcycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl,alkyl-thioaryl, alkyl-aminoaryl, (C₅-C₂)aryl, (C₅-C₂)arylalkyl or(C₅-C₁₂)arylalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S, and optionally substituted with halo, cyano, keto, nitro,hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino,amidine,alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,(C₅-C₆)aryl, —O—(C₅-C₆)aryl, arylcarboxamide, alkylthio orhaloalkylthio;

[0025] R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio,amino, alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising 1 or more heteroatoms selected from O, N and S,and optionally substituted with halo or alkyl;

[0026] R₁₄ is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; oraryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl,alkyl fused aryl-cycloalkyl or aryloxycarboxamide optionally comprising1 or more heteroatoms selected from N, O and S, and optionallysubstituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino,carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide,aryl, arylalkyl, arylcarboxamide, arylalkylcarboxamide, alkylthio orhaloalkylthio;

[0027] R₁₅ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio,amino, alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising 1 or more heteroatoms selected from O, N and S;and

[0028] W is O or S; or C or N optionally substituted with H, alkyl oraryl.

[0029] In a preferred embodiment, X is N and Y is O. In anotherpreferred embodiment, X is O and Y is N. According to several preferredembodiments, R₁₃ is an optionally substituted phenyl or benzyl; pyridyl,piperidinyl, alkyl or H or a fused ring system such as3,4-methylenedioxybenzyl; R₁₄ is optionally substituted amino or anarylalkyloxycarboxamide such as benzyloxycarboxamide; and R₁₅ is H orhalo.

[0030] Preferably, R₂ is isopropyl and R₃ is H.

[0031] In a preferred embodiment of the invention, R₁ is an optionallysubstituted aryl or arylalkyl group, such as a α,α-dimethylbenzyl,benzyl or phenyl group. According to several preferred embodiments, thebenzene ring is substituted with an alkyl, such as methyl; with ahaloalkyl, such as trifluoromethyl; or with a dialkylamino, preferablydimethylamino. In yet another embodiment, R₁ is a fused arylalkyl groupsuch as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl. such as 3,4-methylenedioxybenzyl. In anotherembodiment, R₁ is an alkyl group, preferably (C₁-C₈)alkyl, eitherstraight chain or branched, such as methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, t-butyl, etc.

[0032] The present intention also provides compounds of the formula(Group III):

[0033] wherein X, Y, R₁, R₂, R₃ and B are as described above; and

[0034] R₆ is of formula (I):

[0035] where m is 0 or 1; n is 0 or 1;

[0036] D is a direct bond or an amino acid selected from, but notlimited to, proline, isoleucine, cyclohexylalanine, cysteine optionallysubstituted at the sulfur with alkyl, alkenyl or phenyl optionallysubstituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio;phenylalanine, homo-phenylalanine, dehydrophenylalanine,indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acidoptionally substituted with alkyl, alkenyl or phenyl optionallysubstituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio;tryptophan, tyrosine, serine or threonine optionally substituted withalkyl or aryl; histidine methionine, valine, norvaline, norleucine,octahydroindole-2-carboxylic acid; asparagine, glutamine, ornithine andlysine optionally substituted at the side chain nitrogen with alkyl,alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl,dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl,arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkylfused aryl-cycloalkyl optionally comprising 1 or more heteratomsselected from N, O and S;

[0037] A is a direct bond, —C(O)—, —NH—C(O)—, —S(O)₂—, —OC(O)— or —C—;and

[0038] R₁₄ is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; oraryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl oralkyl fused aryl-cycloalkyl optionally comprising 1 or more heteratomsselected from N, O and S, and optionally substituted with alkyl, halo,alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl,haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl,arylcarboxamide, alkylthio or haloalkylthio.

[0039] Alternatively, R₆ is of formula (II):

[0040] where

[0041] W is S or O;

[0042] R₈ is alkylamino, dialkylamino or amino;

[0043] R₉ is H, alkyl or halo.

[0044] In a preferred embodiment, X is N and Y is O. In anotherpreferred embodiment, X is O and Y is N. According to one embodiment,where R6 is of formula (I), m is 1, n is 0. In another embodiment, m andn are 1. Preferably, R₁₄ is benzyl, A is —OC(O)— and D is Val.

[0045] Preferably, R₂ is isopropyl and R₃ is H.

[0046] In a preferred embodiment of the invention, R₁ is an optionallysubstituted aryl or arylalkyl group, such as a α,α-dimethylbenzyl,benzyl or phenyl group. According to several preferred embodiments, thebenzene ring is substituted with an alkyl, such as methyl; with ahaloalkyl, such as trifluoromethyl; or with a dialkylamino, preferablydimethylamino. In yet another embodiment, R₁ is a fused arylalkyl groupsuch as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment,R₁ is an alkyl group, preferably (C₁-C₈) alkyl, either straight chain orbranched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,t-butyl, etc.

[0047] According to one embodiment, W is S; R₈ is amino and R₉ is H.

[0048] In yet a further embodiment of the invention of Group (III)compounds, R₆ is aryl, arylalkyl, cycloalkyl or alkylcycloalkyl.According to one embodiment, R₆-B is Cbz.

[0049] The present invention further provides compounds of the formula(Group IV):

[0050] wherein

[0051] X, Y, R₁, R₂ and R₃ are as described above;

[0052] R₁₀ is (C₅-C₆)aryl, (C₅-C₆)arylalkyl, (C₅-C₆)arylalkenyl,cycloalkyl, fused aryl-cycloalkyl optionally comprising one or moreheteroatoms selected from N, S and non-peroxide O, and optionallysubstituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamide, alkylthio or haloalkylthio;

[0053] D is a direct bond, —C(O)—, or an amino acid selected from, butnot limited to, proline, isoleucine, cyclohexylalanine, cysteineoptionally substituted at the sulfur with alkyl, alkenyl or phenyloptionally substituted with halo, cyano, nitro, haloalkyl, amino,aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine,indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acidoptionally substituted with alkyl, alkenyl or phenyl optionallysubstituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio;tryptophan, tyrosine, serine or threonine optionally substituted withalkyl or aryl; histidine methionine, valine, norvaline, norleucine,octahydroindole-2-carboxylic acid; asparagine, glutamine, ornithine andlysine optionally substituted at the side chain nitrogen with alkyl,alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl,dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl,arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkylfused aryl-cycloalkyl optionally comprising 1 or more heteratomsselected from N, O and S;

[0054] A is a direct bond, —C(O)—, —NH—C(O)—, —S(O)₂—, —NH—S(O)₂—,—S(O)₂—NH—, —OC(O)NH—, —OC(O)— or —C—; and R₁₄, is as described above.

[0055] In a preferred embodiment, X is N and Y is O. In anotherpreferred embodiment, X is O and Y is N. Preferably, D is Val, A is—OC(O)— and R₁₄ is aryl or arylalkyl such as benzyl. In a preferredembodiment, R₁₀ is (C₅-C₆)aryl or (C₅-C₆)arylalkyl, preferably benzyl,or a fused aryl-cycloalkyl such as an indanyl group. According toanother preferred embodiment, D is —C(O)—, and R₁₄—A is pyrrole.

[0056] Preferably, R₂ is isopropyl and R₃ is H.

[0057] In a preferred embodiment of the invention, R₁ is an optionallysubstituted aryl or arylalkyl group, such as α,α-dimethylbenzyl, benzylor phenyl group. According to several preferred embodiments, the benzenering is substituted with an alkyl, such as methyl; with a haloalkyl,such as trifluoromethyl; or with a dialkylamino, preferablydimethylamino. In yet another embodiment, R₁ is a fused arylalkyl groupsuch as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment,R₁ is an alkyl group, preferably (C₁-C₈)alkyl, either straight chain orbranched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,t-butyl, etc.

[0058] The present invention additionally provides compounds of theformula (Group V):

[0059] wherein

[0060] X, Y, R₁, R₂, R₃, R′₂ and R′₃ are as described above; and

[0061] R₁₁, R₁₂ and E together form a monocyclic or bicyclic ringcomprising 5-10 atoms selected from C, N, S and O; said ring containing1 or more keto groups; and optionally substituted with halo, cyano,nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl,alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido,alkylthio, haloalkylthio; cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, (C₅-C₁₂)aryl, (C₅-C₁₂)arylalkyl,((C₅-C₁₂)arylalkyl)OC(O)NH— or (C₅-C₁₂)arylalkenyl optionally comprisingone or more heteroatoms selected from N, S and non-peroxide O, andoptionally substituted with halo, cyano, nitro, haloalkyl, amino,aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, —C(O)O(alkyl), —C(O)(alkyl), alkylcarboxamido,alkylthio or haloalkylthio.

[0062] In a preferred embodiment, X is N and Y is O. In anotherpreferred embodiment, X is O and Y is N.

[0063] Preferably, R₂ is isopropyl and R₃ is H.

[0064] In a preferred embodiment of the invention, R₁ is an optionallysubstituted aryl or arylalkyl group, such as a α,α-dimethylbenzyl,benzyl or phenyl group. According to several preferred embodiments, thebenzene ring is substituted with an alkyl, such as methyl; with ahaloalkyl, such as trifluoromethyl; or with a dialkylamino, preferablydimethylamino. In yet another embodiment, R₁ is a fused arylalkyl groupsuch as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment,R₁ is an alkyl group, preferably (C₁-C₈)alkyl, either straight chain orbranched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,t-butyl, etc.

[0065] According to one embodiment of the invention, R₁₁, R₁₂, and Etogether form a ring structure of formulas (I) or (Ia):

[0066] wherein A is as described above for Group (IV);

[0067] V₁ V₂, V₃ and V₄ are independently or together C or N;

[0068] where V₃ is C; R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy,carboxyl, alkylthio, amino, alkylamino, dialkylamino; or aryl,arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl- cycloalkyl or alkylfused aryl-cycloalkyl optionally comprising 1 or more heteroatomsselected from O, N and S, and optionally substituted with halo or alkyl;

[0069] R₁₄ is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; oraryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl oralkyl fused aryl-cycloalkyl, arylalkylxoxycarbonyl orarylalkylcarboxamide optionally comprising 1 or more heteroatomsselected from N, O and S, and optionally substituted with alkyl, halo,alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl,haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl,arylcarboxamide, alkylthio or haloalkylthio; and

[0070] W₁, W₂ and W₃ are independently selected from N optionallysubstituted with alkyl; C, S and O.

[0071] According to one preferred embodiment, V₄ is N; and V₁, V₂ and V₃are C. Preferably, R₁₃ is H or halo; R₁₄—A is CbzNH, amino or H; and R′₂and R₁₃ are H. Preferably, R₁₁, R₁₂ and E together form a ring offormula (I). In a particular embodiment, R₁₃ is H or F; and R₁₄—A— is Hor H₂N—. Where R₁₁, R₁₂ and E together form a ring of formula (Ia), W₁is preferably S, and W₂ and W₃ are C.

[0072] In another embodiment, R₁₁, R₁₂ and E together form a ring offormula (II)

[0073] wherein A, R₁₃ and R₁₄ are as described above;

[0074] Preferably, R′₂ and R′₃ are H. According to one embodiment, R₁₃is 1-piperidinyl; and R₁₄—A is CbzNH. Alternatively, R₁₃ is H; and R₁₄—Ais amino, alkylamino or dialkylamino. In another preferred embodiment,R₁₃ is halo; and R₁₄—A is CH₃—O—C(O)—. In yet another embodiment, R₁₃ isH; and R₁₄—A is CbzNH.

[0075] According to another embodiment of the invention, R₁₁, R₁₂ and Eform a ring of formula (III) or (IV):

[0076] wherein

[0077] A is a direct bond, —C— or —C(O)—;

[0078] R₁₃, R₁₄ and R₁₅ are as defined above.

[0079] According to a particular embodiment, R₁₁, R₁₂ and E form a ringof formula (III); and —A—R₁₃ is —C(O)phenyl; R₁₅ is H; and R′₂ and R′₃are H.

[0080] In another embodiment, R₁₁, R₁₂ and E form a ring of formula(IV); and —A—R₁₃ is —C(O)phenyl; R₁₅ is H; and R′₂ and R′₃ and H.

[0081] In another embodiment of the invention, R₁₁, R₁₂ and E form aring of formula (V):

[0082] wherein (V)

[0083] W is S, SO, SO₂ or C;

[0084] n is 0, 1 or 2;

[0085] R₁₃ and R₁₄ are defined above; and

[0086] G is —NHC(O)—, —OC(O)NH—, —C(O)—, —NHS(O)₂— or a direct bond.

[0087] According to one embodiment, n is 0 and W is S, where preferablyR₁₄—G is H. Preferably, R₁₃ is optionally substituted benzyl or phenyl.

[0088] In another embodiment, n is 1 and W is C. Preferably, R₁₄—G is anarylalkyloxycarboxamide, for example, CbzNH—. In a preferred embodiment,R₁₃ is H or phenyl substituted with halo. Preferably, R′₂ and R′₃ are H.

[0089] The invention further provides compounds wherein R₁₁, R₁₂ and Eform a ring of formulas (VI), (VIa), (VII) or (VIII):

[0090] wherein

[0091] R₁₃ is as defined above, or is ═CH—R₁₅ or R₁₅ where R₁₅ ispyridinyl, phenyl or benzyl optionally substituted with halo,dialkylamino or —C(O)OCH₃;

[0092] R₁₄ and R′₁₄ are independently or together H, alkyl, alkenyl,CH₃C(O)—; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fusedaryl-cycloalkyl or alkyl fused aryl-cycloalkyl, aryloxycarbonyl orarylalkyloxycarbonyl optionally comprising 1 or more heteratoms selectedfrom N, O and S, and optionally substituted with alkyl, halo, alkoxy,amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy,carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide,alkylthio or haloalkylthio; and

[0093] R₁₆, R₁₇, R′₁₆ and R′₁₇ are independently or together H, alkyl,alkenyl, alkylthio, alkylthioalkyl; or cycloalkyl, cycloalkenyl,alkylcycloalkyl, aryl, arylalkyl or arylalkenyl optionally substitutedwith guanidine, carboalkoxy, hydroxyl, haloalkyl, alkylthio,akylguanidine, dialkylguanidine or amidine.

[0094] Preferred compounds are of formula (VI) or (VIa) where R₁₃ is═CH—R₁₅ or R₁₅; and R₁₄ is H, alkyl, CH₃C(O)—, Cbz or benzyl optionallysubstituted with alkyl, halo or alkylamino; or 3,4-methylenedioxybenzylor 3,4-ethylenedioxybenzyl; and R′₂ and R′₃ are H. Preferably, R′₃ is═CHR₁₅ where R₁₅ is phenyl or benzyl optionally substituted with halo or—C(O)CH₃.

[0095] In a further embodiment, R₁₁, R₁₂ and E form a ring of formula(IX) or (IXa):

[0096] wherein

[0097] U, V, W and Y are independently or together N, C, C(O), N(R₁₃)where R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio,amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising 1 or more heteroatoms selected from O, N and S,and optionally substituted with halo or alkyl; N(R₁₄) where R₁₄ is H,alkyl, alkenyl, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fusedaryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1or more heteratoms selected from N, O and S, and optionally substitutedwith alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy,alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl,arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; or C(R₁₆)(R₁₇)where R₁₆ and R₁₇ are independently or together H, alkyl, alkylthio,alkylthioalkyl; a carboxylic acid ester of the formula —(CH₂)_(m)C(O)ORor an N-substituted alkylamide of the formula —(CH₂)_(m)C(O)NRR′ where mis 1 to 6 and R and R′ are independently or together H or alkyl; oraryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl oralkyl fused aryl-cycloalkyl optionally comprising one or moreheteroatoms selected from N, S and non-peroxide O and optionallysubstituted with amino, alkylamino, dialkylamino, guanidine,carboalkoxy, keto, hydroxyl, alkyl, haloalkyl, alkylthio,alkylguanidine, dialkylguanidine or amidine; or together form a cyclicring structure comprising 4-8 atoms selected from C, N, O and S.

[0098] In one preferred embodiment, U is C(R₁₆)(R₁₇), V is N, W isN(R₁₄) and Y is C(O), where preferably R′₂ and R′₃ are H; R₁₆ is phenylor benzyl; R₁₇ is H; and R₁₄ is H or benzyl optionally substituted withalkyl, halo, or alkylamine.

[0099] In another preferred embodiment, U is C(O); V is N, W is N,N(R₁₃) or N(R₁₄); and Y is C(R₁₆)(R₁₇), where preferably R′₂ and R′₃ areH; R₁₄ is H; R₁₆ is H, alkyl, optionally substituted aryl or arylalkyl,preferably benzyl or phenyl optionally substituted with dialkylamino orhydroxyl; pyridinyl, methylene pyridinyl; fused aryl such as an indolyl,indolemethylene; or a carboxylic acid ester or N-substituted alkylamide, as defined above; and R₁₇ is H, alkyl, succinimidyl, aryl orarylalkyl.

[0100] In yet another preferred embodiment, U is C(O), V is N, W is N,N(R₁₃) or N(R₁₄); and Y is N(R₁₃), where preferably R′₂ and R′₃ are H;W is NH; R₁₃ is arylalkyl; and R₁₄ is H.

[0101] In a further embodiment, U is C(R₁₆)(R₁₇); V is N; W is N orN(R₁₃); and Y is C(O). Preferably, R₁₃ and R₁₆ are aryl; and R₁₇ is H.

[0102] Where R₁₁, R₁₂ and E form a ring of formula (IXa); W is typicallyN(R₁₃) where R₁₃ is aryl or cycloalkyl such as piperidinyl.

[0103] In another embodiment, R₁₆ and R₁₇ form a cyclic ring structure,such as a cyclopentyl or cyclohexyl group.

[0104] The invention further provides compounds of the formula (GroupVI):

[0105] wherein X, Y, R₁, R₂ and R₃ are as described above, and R₁₁, R₁₂and E together form a ring of formula (X):

[0106] where U and V are independently or together N, C, N(R₁₃) whereR₁₃ is H, alkyl, alkoxy, carboalkoxy, carboxyl, alkylthio, amino,alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising 1 or more heteroatoms selected from O, N and S; orC(R₁₆)(R₁₇) where R₁₆ and R₁₇ are as defined above; and

[0107] and n is 1 or 2.

[0108] The present invention further provides methods of synthesizingcompounds of formula (A):

[0109] where in (A)

[0110] Z′ is defined below;

[0111] R₁ is alkyl or alkenyl optionally substituted with 1-3 halo orhydroxyl; -alkyl- C(O)OCH₃; alkylamino, dialkylamino, alkyldialkylamino;or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C₅-C₁₂)aryl,(C₅-C₁₂)arylalkyl, (CS-C₁₂)arylalkenyl, fused(C₅-C₁₂)aryl-cycloalkyl orfused(C₅-C₁₂)aryl-cyclalkylalkyl optionally comprising 1-4 heteroatomsselected from N, O and S, and optionally substituted with halo, cyano,nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamide, (C₅-C₆)aryl, —O—(C₅-C₆)aryl,arylcarboxamide, alkylthio or haloalkylthio;

[0112] X and Y are independently O, S or N, wherein N is optionallysubstituted with alkyl or alkenyl optionally substituted with 1-3 haloatoms; (C₅-C₆)aryl, arylalkyl or arylalkenyl optionally comprising 1-3heteroatoms selected from N, O and S, and optionally substituted withhalo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl,carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio; and

[0113] R₂ and R₃ are independently or together H; alkyl or alkenyloptionally substituted with 1-3 halo, hydroxyl , thio, alkylthio, amino,alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl,guanidinyl, or amidylguanidine; —RCOR′, —RCOOR′, —RNR′R″R° or—RC(O)NR′R″ where R is alkyl or alkenyl, and R′, R″ and R° areindependently H, alkyl, alkenyl, cycloalkyl or (C₅-C₆)aryl; orcycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl- oxyaryl,alkyl-thioaryl, alkyl-aminoaryl, (C₅-C₁₂)aryl, (C₅-C₁₂)arylalkyl or(C₅-C₁₂)arylalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S, and optionally substituted with halo, cyano, keto, nitro,hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine,alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,(C₅-C₆)aryl, —O—(C₅-C₆)aryl, arylcarboxamide, alkylthio orhaloalkylthio;

[0114] comprising the steps of:.

[0115] (a) reacting a compound of formula (B):

[0116] wherein M is Li or MgBr,

[0117] with an aldehyde of formula (C):

[0118] where [PrG₁] is a protecting group;

[0119] (b) removing the protecting group from the resulting alcohol (D)

[0120] (c) coupling the alcohol obtained from step (b) with an acid offormula (E):

Z′—COOH  (E)

[0121] and

[0122] (d) oxidizing the resulting product and further, if desired,removing the protecting group to yield the final compound.

[0123] According to one embodiment, the protecting group [PGR₁] isremoved from alcohol (D) by reacting the aldehyde of formula (C) withhydrochloric acid in dioxane. The protecting group [PGr₁] may be anysuitable group, preferably Boc.

[0124] According to another embodiment, the oxidation step of (d) isperformed using Dess Martin reagent.

[0125] In a further embodiment, the compound of formula (B) issynthesized by:

[0126] (e) treating an acid of the formula (R₁)COOH with thionylchloride or oxalyl chloride;

[0127] (f) treating the resulting acid chloride with hydrazine to yielda hydrazide of the formula (R₁)CONHNH₂;

[0128] (g) reacting the hydrazide with triethyl orthoformate ortrimethyl orthoformate and TsOH to yield a oxadiazole of the formula(F):

[0129] and

[0130] (h) treating the oxadiazole with butyllithium and further, isdesired, reacting with MgBr.OEt₂ to yield the compound B.

[0131] In one embodiment, Z′ is

[0132] wherein

[0133] A is a direct bond, —C(O)—, —NH—C(O)—, —S(O)₂—, —NH—S(O)₂—,—OC(O)—, —C— or an amino acid selected from proline, isoleucine,cyclohexylalanine, cysteine optionally substituted at the sulfur withalkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro,haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine,indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acidoptionally substituted with alkyl, alkenyl or phenyl optionallysubstituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl,dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio;tryptophan, tyrosine, serine or threonine optionally substituted withalkyl or aryl; histidine, methionine, valine, norvaline, norleucine,octahydroindole-2-carboxylic acid; asparagine, glutamine, omithine andlysine optionally substituted at the side chain nitrogen with alkyl,alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl,dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl,arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkylfused aryl-cycloalkyl optionally comprising 1 or more heteroatomsselected from N, O and S; and

[0134] R₄ is H, alkyl, alkenyl, or alkynyl; or cycloalkyl,alkylcycloalkyl, (C₅-C₁₂)aryl, (C₅-C₁₂)arylalkyl, fused(C₅-C₁₂)aryl-cycloalkyl or fused (C₅-C₁₂)aryl-cycloalkylalkyl optionallycomprising one or more heteroatoms selected from N, O and S, andoptionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro,hydroxyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl,haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl,arylcarboxamido, alkylthio or haloalkylthio or is absent; or

[0135] Z′ may be

[0136] wherein

[0137] R′₂ and R′₃ are independently or together H; alkyl or alkenyloptionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino,alkylarnino, dialkylamino, alkylguanidinyl, dialkylguanidinyl,guanidinyl or amidylguanidine; —RCOR′, —RCOOR′, —RNR′R″R° or —RC(O)NR′R′where R is alkyl or alkenyl, and R′, R″ and R° are independently H,alkyl, alkenyl, cycloalkyl or (C₅-C₆)aryl; or cycloalkyl,alkylcycloalkyl, alkenylcycloalkyl, alkyloxyaryl, alkyl-thioaryl,alkyl-aminoaryl, (C₅-C₁₂)aryl, (C₅-C₁₂)arylalkyl or (C₅-C₁₂)arylalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S, andoptionally substituted with halo, cyano, keto, nitro, hydroxyl,haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine,dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy,haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C₅-C₆)aryl,—O—(C₅-C₆)aryl, arylcarboxamide, alkylthio or haloalkylthio;

[0138] R₁₃ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio,amino, alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising 1 or more heteroatoms selected from O, N and S,and optionally substituted with halo or alkyl;

[0139] R₁₄ is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; oraryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl,alkyl fused aryl-cycloalkyl, or aryloxycarboxamide optionally comprising1 or more heteroatoms selected from N, O and S, and optionallysubstituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino,carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide,aryl, arylalkyl, arylcarboxamide, arylalkylcarboxamide, alkylthio orhaloalkylthio; and

[0140] R₁₅ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio,amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl,alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyloptionally comprising 1 or more heteroatoms selected from O, N and S.

[0141] In yet a further embodiment, Z′ is:

[0142] where m is 0 or 1; n is 0 or 1,

[0143] D is a direct bond or an amino acid selected from proline,isoleucine, cyclohexylalanine, cysteine optionally substituted at thesulfur with alkyl, alkenyl or phenyl optionally substituted with halo,cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy,haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide,alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine,dehydrophenylalanine, indoline-2-carboxylic acid;tetrahydrosioquinoline-2-carboxylic acid optionally substituted withalkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro,haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio orhaloalkylthio; tryptophan, tyrosine, serine or threonine optionallysubstituted with alkyl or aryl; histidine methionine, valine, norvaline,norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine,omithine and lysine optionally substituted at the side chain nitrogenwith alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl,alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl,or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkylor alkyl fused aryl- cycloalkyl optionally comprising 1 or moreheteroatoms selected from N, O and S; and

[0144] A′ is a direct bond, —C(O)—, —NH—C(O)—, —S(O)₂—, —NH—S(O)₂—,—OC(O)— or —C—.

[0145] In yet another embodiment, Z′ is:

[0146] where

[0147] W is S or O;

[0148] R₈ is alkylamino, dialkylamino or amino; and

[0149] R₉ is H, alkyl or halo; or

[0150] Z′ is:

[0151] wherein

[0152] R₁₀ is (C₅-C₆)aryl, (C₅-C₆)arylalkyl, (C₅-C₆)arylalkenyl,cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fusedaryl-cycloalkyl optionally comprising one or more heteroatoms selectedfrom N, S and non-peroxide O, and optionally substituted with halo,cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy,alkylcarboxamide, alkylthio or haloalkylthio.

[0153] In a preferred embodiment, Z′ is:

[0154] wherein

[0155] R₁₁, R₁₂ and E together form a monocyclic or bicyclic ringcomprising 5-10 atoms selected from C, N, S and O; said ring containing1 or more keto groups; and optionally substituted with halo, cyano,nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl,alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,alkylthio, haloalkylthio or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, (C₅-C₁₂)aryl, (C₅-C₁₂)arylalkyl,((C₅-C₁₂)arylalkyl)OC(O)NH— or (C₅-C₁₂)arylalkenyl optionally comprisingone or more heteroatoms selected from N, S and non-peroxide O, andoptionally substituted with halo, cyano, nitro, haloalkyl, amino,aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy,carboxyl, carboalkoxy, —C(O)O(alkyl), —C(O)(alkyl), alkylcarboxamide,alkylthio or haloalkylthio.

[0156] In a preferred embodiment, the invention provides a method ofsynthesizing a compound of formula (G):

[0157] wherein

[0158] T is H or NH₂;

[0159] R₁ is alkyl or alkenyl optionally substituted with 1-3 halo orhydroxyl; a carboxylic acid ester such as -alkyl—C(O)OCH₃; alkylamino,dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl,alkenylcycloalkyl, (C₅-C₁₂)aryl, (C₅-C₁₂)arylalkyl, (C₅-C₁₂)arylalkenyl,fused (C₅-C₁₂)aryl-cycloalkyl or fused(C₅-C₁₂)arylcyclalkylalkyloptionally comprising 1-4 heteroatoms selected from N, O and S, andoptionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl,amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl,alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide,(C₅-C₆)aryl, —O—(C₅-C₆)aryl, arylcarboxamide, alkylthio orhaloalkylthio; and

[0160] Ar is an aryl or arylalkyl optionally substituted with H, alkyl,amino, alkylamino, dialkylamino, halo or hydroxyl;

[0161] comprising the steps of:

[0162] (a) reacting a compound of formula (B):

[0163] wherein M is Li or MgBr;

[0164] with an aldehyde of formula (C):

[0165] where [PrG₁] is a protecting group;

[0166] (b) removing the protecting group from the resulting alcohol (D)

[0167] (c) coupling the alcohol obtained from step (b) with an acid offormula (H):

[0168] wherein T′ is H or [PGr₂]NH, where [PGr₂] is a protecting group;

[0169] (d) oxidizing the resulting product to yield a ketone of formula(J):

[0170] and further, when T′ is [PGr₂]NH,

[0171] (e) removing the protecting group [PGr₂] to yield the compound offormula (G). Preferably, [PGr₂] is Cbz.

[0172] As used herein, the term “optionally substituted” means, whensubstituted, mono to fully substituted.

[0173] As used herein, the term “independently” means that thesubstituents may be the same or different.

[0174] As used herein, the term “alkyl” means C₁-C₁₅, however,preferably C₁-C₈.

[0175] As used herein, the term “alkenyl” means C₁-C₁₅, however,preferably C₁-C₈.

[0176] As used herein, the term “alkynyl” means C₁-C₁₅, however,preferably C₁-C₈.

[0177] It will be understood that alkyl, alkenyl and alkynyl groups,whether substituted or unsubstituted, may be linear or branched.

[0178] As used herein, the term “aryl,” unless otherwise stated, meansaryl groups preferably comprising 5 to 12 carbons, and more preferably 5to 6 carbons. Unless otherwise indicated, the term includes both mono-and bi-cyclic fused ring systems. As used herein, where the term“arylalkyl” is defined by the general formula (C_(x)-C_(y))arylalkyl, xand y refer to the number of carbons making up the aryl group. The alkylgroup is as defined above. The term include mono-substituted alkylgroups (e.g., benzyl), as well as di-substituted alkyl groups such as-alkyl(aryl)₂ (e.g., —CH(phenyl)₂). The terms arylalkyl and alkyl fusedarylcycloalkyl include (α,α)-disubstituted groups such as, for example,(α,α)-disubstituted benzyl and (α,α)-disubstituted3,4-methylenedioxybenzyl groups, wherein the α substituents arepreferably alkyl groups such as methyl, ethyl or propyl. Specificexamples include (α,α)-dimethylbenzyl and(α,α)-dimethyl-3,4-methylenedioxybenzyl.

[0179] As used herein, the term “arylalkenyl” includes aryl groups wherethe alkenyl group comprises 1-3 or more double bonds. Exemplaryarylalkenyl groups include —CH═CH₂-aryl and —CH═CH-aryl, where aryl ispreferably phenyl.

[0180] As used herein, the term “cycloalkyl,” unless otherwise stated,means cycloalkyl groups preferably comprising 3 to 12 carbons, and morepreferably 3 to 6 carbons. Unless otherwise indicated, the term includesboth mono-, bi- and tri-cyclic fused ring systems.

[0181] As used herein, the term “Cbz” means benzyloxycarbonyl.

[0182] As used herein, the term “carboxamide” is synonymous with amide;i.e., a group of the formula —NHC(O)—.

[0183] As used herein, the term “oxycarboxamide” means a group of theformula —O—C(O)NH—.

[0184] As used herein, the term “oxycarbonyl” means a group of theformula —OC(O)—.

[0185] Pharmaceutically acceptable salts of the compounds describedabove are within the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0186]FIG. 1 is a schematic representation of the synthesis of compoundsof Group I.

[0187]FIG. 2 is a schematic representation of the synthesis of compoundsof Group I.

[0188]FIG. 3 is a schematic representation of the synthesis of compoundsof Group I.

[0189]FIG. 4 is a schematic representation of the synthesis of compoundsof Group I.

[0190]FIG. 5 is a schematic representation of the synthesis of compoundsof Group II.

[0191]FIG. 6 is a schematic representation of the synthesis of compoundsof Group II.

[0192]FIG. 7 is a schematic representation of the synthesis of compoundsof Group II.

[0193]FIG. 8 is a schematic representation of the synthesis of compoundsof Group III.

[0194]FIG. 9 is a schematic representation of the synthesis of compoundsof Group III.

[0195]FIG. 10 is a schematic representation of the synthesis ofcompounds of Group IV

[0196]FIG. 11 is a schematic representation of the synthesis ofcompounds of Group V.

[0197]FIG. 12 is a schematic representation of the synthesis ofcompounds of Group V.

[0198]FIG. 13 is a schematic representation of the synthesis ofcompounds of Group V.

[0199]FIG. 14 is a schematic representation of the synthesis ofcompounds of Group V.

[0200]FIG. 15 is a schematic representation of the synthesis ofcompounds of Group V.

[0201]FIG. 16 is a schematic representation of the synthesis ofcompounds of Group V.

[0202]FIG. 17 is a schematic representation of the synthesis ofcompounds of Group V.

[0203]FIG. 18 is a schematic representation of the synthesis ofcompounds of Group V.

[0204]FIG. 19 is a schematic representation of the synthesis ofcompounds of Group V.

[0205]FIG. 20 is a schematic representation of the synthesis ofcompounds of Group V.

[0206]FIG. 21 is a schematic representation of the synthesis ofcompounds of Group V.

[0207]FIG. 22 is a schematic representation of the synthesis ofcompounds of Group V.

[0208]FIG. 23 shows the activity of certain compounds of Group I.

[0209]FIG. 24 shows the activity of certain compounds of Group I.

[0210]FIG. 25 shows the activity of certain compounds of Group I.

[0211]FIG. 26 shows the activity of certain compounds of Group I.

[0212]FIG. 27 shows the activity of certain compounds of Group I.

[0213]FIG. 28 shows the activity of certain compounds of Group II andIII.

[0214]FIG. 29 shows the activity of certain compounds of Groups II, IIIand IV.

[0215]FIG. 30 shows the activity of certain compounds of Group V.

[0216]FIG. 31 shows the activity of certain compounds of Group V.

[0217]FIG. 32 shows the activity of certain compounds of Group V.

[0218]FIG. 33 shows the activity of certain compounds of Group V.

[0219]FIG. 34 shows the activity of certain compounds of Group V.

[0220]FIG. 35 shows the activity of certain compounds of Group V.

[0221]FIG. 36 shows the activity of certain compounds of Group V.

[0222]FIG. 37 shows the activity of certain compounds of Group V.

[0223]FIG. 38 shows the activity of certain compounds of Group V.

[0224]FIG. 39 is a schematic representation of the synthesis of certaincompounds of the invention.

DETAILED DESCRIPTION

[0225] The compounds of the present invention have been found to bepotent inhibitors of the serine protease human neutrophil elastase(HNE). They are reversible inhibitors that presumably form a transitionstate intermediate with the active site serine residue. The compoundsare characterized by their low molecular weights, high selectivity withrespect to HNE and stability regarding physiological conditions.Therefore, the compounds can be implemented to prevent, alleviate and/orotherwise treat diseases which are mediated by the degradative effectsassociated with the presence of HNE. Their usage is of particularimportance as they relate to various human treatment in vivo but mayalso be used as a diagnostic tool in vitro.

[0226] The present invention provides, but is not limited to, specificembodiments set forth in the Examples as well as those set forth below.

[0227] The nomenclature for the above embodiments is as follows(although the majority of the embodiments disclosed indicate thestereochemistry of the 2-methylpropyl group having the(S)-configuration, it will be understood that both the (R)-configurationand the racemic (R,S) are within the scope of the invention):

[0228] CE-21572-Oxo-5-(phenyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0229] CE-21583-(S)-[(Benzyloxycarbonyl)amino-(5,6-phenyl-ε-lactam]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0230] CE-2159 2-(R,S)-[6-(Methylene-4-pyridyl)piperazine-2,5-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0231] CE-21603-(R,S)-[(Benzyloxycarbonyl)amino-6-lactam]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0232] CE-2161(Pyridyl-3-carbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0233] CE-2162 4-[1-(2-N-Morpholino)ethyl-3-(R)-benzylpiperazine-2,5-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0234] CE-2163Methylsulfonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0235] CE-2164(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide

[0236] CE-2165N-Acetyl-2-(L)-(2,3-dihydro-1H-indole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide

[0237] CE-21661-Phenyl-1,2,4-triazolidine-3,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0238] CE-2168Phenylsulfonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0239] CE-2170 1-[2-(5-[3-Methylbenzyl]-1,3,4-oxadiazolyl]-2-(S)-[(benzyloxycarbonyl)amino]-3-methylbutan-1-one

[0240] CE-2171(3-Pyridylcarbonyl)-L-valyl-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0241] CE-2172Methylsulfonyl-L-valyl-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0242] CE-21731-(3-Morpholinoethyl)-5-(R)-benzyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0243] CE-21744-(R)-Isopropyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0244] CE-21761-Benzyl-1,2,4-triazolidine-3,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0245] CE-2177(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0246] CE-2178(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,4-methylenedioxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0247] CE-21795-(R,S)-Phenyl-1-methyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0248] CE-21801-(N-(-Morpholinoethyl)-5-(R)-benzyl-2,4-imidazolidinedione-N-[1-(3-[5-(3trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0249] CE-21811-(N-Morpholinoethyl)-5-(S)-benzyl-2,4-imidazolidinedione-N-[1-(3-[5-(3trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0250] CE-21825-(R,S)-Phenyl-1-methyl-2,4-imidazolidinedione-N-[1-(3-[5-(3trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0251] CE-2183Benzyloxycarbonyl-L-valyl-(1,2,3,4-tetrahydroisoquinoline)-3-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]aide

[0252] CE-21841-(N-Morpholinoethyl)-5-(S)-benzyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0253] CE-218 54-Pyridylmethyleneoxycarbonyl-L-valyl-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0254] CE-21864-Pyridylmethyleneoxycarbonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0255] CE-21874-[1-(3,4-Ethylenedioxybenzyl)-3-(S)-benzyl-piperazine-2,5-dione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S )-methylpropyl]acetamide

[0256] CE-21881-Benzyl-4-(S)-benzyl-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0257] CE-21891-Benzyl-2,4-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0258] CE-2190[1-Benzyloxycarbonyl-5-(R)-benzylpiperazin-3-one]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0259] CE-21911-Benzyl-4-(S)-benzyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0260] CE-21921-(N-Morpholinoethyl)-5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0261] CE-21931-(N-Morpholinoethyl)-5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0262] CE-2194[4-(R,S)-(4-Dimethylaminophenyl)1-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0263] CE-2195(Pyrrole-2-carbonyl)-N-[1-(R,S)-indanyl]glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide

[0264] CE-2196(6-(R)-Benzylpiperazin-2-one)-N-1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0265] CE-21974-1-[(3,4-Ethylenedioxybenzyl)-3-(R)-benzylpiperazine-2,5-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0266] CE-21984-(R,S)-Phenyl-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0267] CE-2200[4-(R,S)-(4-Dimethylaminophenyl)]-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0268] CE-2202Isopropyloxycarbonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0269] CE-2203[4-(R)-(3-pyridylmethylene)]-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0270] CE-22041-Benzyloxycarbonyl-(2-(R)-phenylpiperazin-5-one)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0271] CE-2205[4-(R)-(3-pyridylmethylene)]-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0272] CE-2206[4-(R,S)-(4-pyridyl)-4-(R,S)-N-succinimidyl]-2,5-imidazolidinedione-N-[-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0273] CE-2207Isopropyloxycarbonyl-L-valyl-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0274] CE-2208(2-(R)-Phenylpiperazin-5-one)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0275] CE-2209[4-(R,S)-(4-pyridyl)-4-(R,S)-N-succinimidyl1-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0276] CE-2210(N-Benzylcarbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4,-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide

[0277] CE-2211(R,S)-3-Amino-2-oxo-5-phenyl-1,4-(6-2′-chlorobenzodiazepine)-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-propyl]acetamide

[0278] CE-22123-[1-(4-Piperidine)]-benzimidazolidin-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0279] CE-2213Methyloxycarbonyl-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0280] CE-2214 Methyloxycarbonyl-L-valyl-N-[1-(3-[5-(3trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0281] CE-22151,4-Quinazolin-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0282] CE-2216[4-(R,S)-(2-Pyridyl)-4-(R,S)-methyl]-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0283] CE-22172-Oxo-5-(2-pyridyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0284] CE-2218(R,S)-3-Amino-2-oxo-5-(2-pyridyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylpropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0285] CE-22191,4-Quinazolin-2-one-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0286] CE-2220 (2S,5S)-5-Amino-1,2,4,5,6,7-hexahydroazepino-[3.2.1]-indole-4-one-carbonyl-N-[1-(3-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]amide

[0287] CE-2221(R,S)-3-Amino-2-oxo-5-phenyl-1,4-benzodiazepine-N-[1-(3-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0288] CE-2223(R,S)-3-Amino-2-oxo-5-phenyl-1,4-(2′-chlorobenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0289] CE-2224(R,S)-3-Amino-2-oxo-5-(4-chlorophenyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0290] CE-2225(R,S)-3-Amino-2-oxo-5-methyl-1,4-(2′,3′-methylenedioxy-benzodiazepine)-N-[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0291] CE-2226(R,S)-3-Amino-2-oxo-5-methyl-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0292] CE-22274-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0293] CE-22283-(R,S)-Amino-quinolin-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0294] CE-2229(R,S)-3-Amino-2-oxo-5-(2-chlorophenyl)-1,4-(2′-chlorobenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0295] CE-2230(R,S)-3-Benzyloxycarbonylamino-2-oxo-5-(2-chlorophenyl)-1,4-(2′-chlorobenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0296] CE-22314-Spirocyclopentane-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0297] CE-2232Benzyloxycarbonyl-L-valyl-N-(phenyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide

[0298] CE-22332-Oxo-5-(4-piperidinyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0299] CE-22342-(2-Pyridyl)-benzimidazole-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0300] CE-2235(R,S)-3-Amino-2-oxo-5-methyl-1,4-(2′,3′-dimethoxybenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0301] CE-2236(R,S)-3-Amino-2-oxo-5-methyl-1,4-(1-thiophenodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0302] CE-2237 2-Oxo-5-(4-trifluoromethylphenyl)-1,4benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0303] CE-22382,5-Imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0304] CE-22394,4-Dimethyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0305] CE-22404-(S)-(2-Isopropyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0306] CE-22414-Spirocyclohexane-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0307] CE-22422-Oxo-5-phenyl-1,4-(4′-methylbenzodiazepine)-N-1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0308] CE-22434-(R)-(3-Indolemethylene)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0309] CE-22442-Oxo-5-methyl-1,4-(1-thiophenodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0310] CE-22452-Oxo-5-methyl-1,4-(2-phenyl-1-thiophenodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0311] CE-22464-(R)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0312] CE-22474-(R)-(2-N,N-Dimethylcarboxamido)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0313] CE-22482-Oxo-5-(3,4-methylendioxyphenyl)-1,4-benzodiazepine-N-[1-2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0314] CE-2249 4-(R)-(3-Carbomethoxy)propyl-2,5-imidazolidinedione-N-[1(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0315] CE-22502-Oxo-5-(2-methoxyphenyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0316] CE-22512-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0317] CE-22524,4-Diphenyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0318] CE-22534-Spiro-(2-indanyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0319] CE-22542-[(4-Fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0320] CE-22554-(R)-(4-Hydroxybenzyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0321] CE-22564-(R)-(4-Hydroxybenzyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0322] CE-22574-(R)-(2-Imidazolyl)-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0323] CE-22582-Oxo-5-phenyl-1,4-(2′-dimethylaminobenzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0324] CE-22594,4-Diphenyl-2,5-imidazolidinedione-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0325] CE-22602-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0326] CE-22612-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0327] CE-22622-[5-Amino-6-oxo-2-thiophenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0328] CE-22632-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0329] ONO-PO-6902-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0330] ONO-PO-6912-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0331] ONO-PO-6922-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0332] ONO-PO-6932-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide

[0333] ONO-PO-6942-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0334] ONO-PO-6952-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-pyridyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0335] ONO-PO-6962-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0336] ONO-PO-6972-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0337] ONO-PO-6982-[5-Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0338] ONO-PO-6992-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(4-methoxyphenyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0339] ONO-PO-7002-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N[1-(2-[5-(α,α-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0340] ONO-PO-7012-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3,4-dihydroxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0341] ONO-PO-7022-[5-(Methylsulfonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0342] ONO-PO-7032-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-benzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0343] ONO-PO-7042-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-methyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0344] ONO-PO-7052-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-isopropyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0345] ONO-PO-7062-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0346] ONO-PO-7072-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0347] ONO-PO-7084-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0348] ONO-PO-7094-(S)-(2-Isobutyl)-2,5-imidazolidinedione-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0349] ONO-PO-710Methylsulfonyl-L-valyl-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0350] ONO-PO-7112-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0351] ONO-PO-7122-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0352] ONO-PO-713Methylsulfonyl-L-valyl-N-[1-(2-[5-(tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0353] ONO-PO-7142-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0354] ONO-PO-7152-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0355] ONO-PO-7162-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0356] ONO-PO-7172-Oxo-5-(4-chlorophenyl)-1,4-benzodiazepine-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0357] ONO-PO-7182-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide

[0358] ONO-PO-7194-(R)-Isopropyl-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0359] ONO-PO-7204-(R)-Isopropyl-2,5-imidazolidinedione-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0360] ONO-PO-72 12-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide

[0361] ONO-PO-7222-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0362] ONO-PO-7234-(R)-(3-Indolemethylene)-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0363] ONO-PO-7244-(R)-(3-Indolemethylene)-2,5-imidazolidinedione-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0364] ONO-PO-7252-[6-Oxo-2-phenyl-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0365] ONO-PO-7262-[6-Oxo-2-phenyl-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0366] ONO-PO-7272-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide

[0367] ONO-PO-7282-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0368] ONO-PO-7292-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide

[0369] ONO-PO-7302-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0370] ONO-PO-7312-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-α,α-dimethylbenzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0371] ONO-PO-7322-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide

[0372] ONO-PO-7332-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0373] ONO-PO-7342-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0374] ONO-PO-7352-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0375] ONO-PO-7362-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0376] ONO-PO-7372-[6-Oxo-2-phenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide

[0377] The compounds of the present invention are not limited to use forinhibition of human elastase. Elastase is a member of the class ofenzymes known as serine proteases. This class also includes, forexample, the enzymes chymotrypsin, cathepsin G, trypsin and thrombin.These proteases have in common a catalytic triad consisting ofSerine-195, Histidine-57 and Aspartic acid-102 (chymotrypsin numberingsystem). The precise hydrogen bond network that exists between theseamino acid residues allows the Serine-195 hydroxyl to form a tetrahedralintermediate with the carbonyl of an amide substrate. The decompositionof this intermediate results in the release of a free amine and theacylated enzyme. In a subsequent step, this newly formed ester ishydrolyzed to give the native enzyme and the carboxylic acid. It is thiscarboxyl component that helps characterize the specificity for theenzyme. In the example in which the carboxyl component is a peptide, thealpha-substituent of the amino acid is predominately responsible for thespecificity toward the enzyme. Utilizing the well accepted subsetnomenclature by Schechter and Berger (Biochem. Biophy. Res. Commun.,27:157 (1967) and Biochem. Biophys. Res. Commun., 32:898 (1968)), theamino acid residues in the substrate that undergo the cleavage aredefined as P₁ . . . P_(n) toward the N-terminus and P₁′ . . . P_(n)′toward the C-terminus. Therefore, the scissile bond is between the P₁and the P₁′ residue of the peptide subunits. A similar nomenclature isutilized for the amino acid residues of the enzyme that make up thebinding pockets accommodating the subunits of the substrate. Thedifference is that the binding pocket for the enzyme is designated by S₁. . . S_(n) instead of P₁ . . . P_(n) as for the substrate.

[0378] The characteristics for the P₁ residue defining serine proteinasespecificity is well established. The proteinases may be segregated intothree subclasses: elastases, chymases and tryptases based on thesedifferences in the P₁ residues. The elastases prefer small aliphaticmoieties such as valine whereas the chymases and tryptases prefer largearomatic hydrophobic and positively charged residues respectively.

[0379] One additional proteinase that does not fall into one of thesecategories is propyl endopeptidase. The P₁ residue defining thespecificity is a proline. This enzyme has been implicated in theprogression of memory loss in Alzheimer's patients. Inhibitorsconsisting of α-keto heterocycles have recently been shown to inhibitpropyl endopeptidase; Tsutsumi et al., J. Med Chem., 37:3492-3502(1994). By way of extension, α-keto heterocycles as defined herein allowfor an increased binding in P′ region of the enzyme. TABLE 1 P₁Characteristics for Proteinase Specificity Proteinase ClassRepresentative Enzyme P₁ Characteristic Elastases Human NeutrophilElastase small aliphatic residues Chymases alpha-Chymotrypsin, aromaticor large Cathepsin G hydrophobic residues Tryptases Thrombin, Trypsin,Urokinase, positively Plasma Kallikrein, charged Plasminogen Activator,residues Plasmin Other Prolyl Endopeptidase proline

[0380] Since the P₁ residue predominately defines the specificity of thesubstrate, the present invention relates to P₁-P_(n)′ modifications,specifically, certain alpha-substituted keto- heterocycles composed of1,3,4 oxadiazoles, 1,2,4-oxadiazoles, 1,3,4-thiadiazoles,1,2,4-thiadiazoles, 1-substituted, and 4-substituted 1,2,4-triazoles. Byaltering the alpha-substituent and the substituent on the heterocycle,the specificity of these compounds can be directed toward the desiredproteinase (e.g., small aliphatic groups for elastase).

[0381] The efficacy of the compounds for the treatment of variousdiseases can be determined by scientific methods which are known in theart. The following are noted as examples for HNE mediated conditions:

[0382] for acute respiratory distress syndrome, the method according tohuman neutrophil elastase (HNE) model (AARD, 141:227-677 (1990)); theendotoxin induced acute lung injury model in minipigs (AARD, 142:782-788(1990));or the method according to human polymorphonuyclearelastase-induced lung hemorrage model in hamsters (European PatentPublication No. 0769498) may be used;

[0383] in ischemia/reperfusion, the method according to the canine modelof reperfusion injury (J. Clin. Invest., 81: 624-629 (1988)) may beused;

[0384] The compounds of the present invention, salts thereof, and theirintermediates can be prepared or manufactured as described herein or byvarious processes known to be present in the chemical art (see also, WO96/16080). For example, compounds of Group I may be synthesizedaccording to the schemes set forth in FIGS. 1-2 (1,3,4 oxadiazoles) andFIGS. 3-4 (1,2,4 oxadiazoles). FIGS. 5-7 describe the synthesis ofcompounds of Group II. FIGS. 8-9 describe the synthesis of compounds ofGroup III; FIG. 10 describes synthesis of Group IV compounds. Theseveral classes of Group V compounds are described in FIGS. 11-22.

[0385] Alternatively, the compounds of the present invention may beprepared as described in FIG. 39. The 2-substituted 1,3,4-oxadiazole (3)may be prepared via formation of the acid chloride from an acid (1)utilizing, for example, thionyl chloride or oxalyl chloride, followed bytreatment with hydrazine in a suitable solvent to yield the hydrazide(2). Reaction of (2) with triethyl orthoformate or trimethylorthoformate and TsOH gives the requisite 2-substituted 1,3,4-oxadiazole(3).

[0386] Formation of the compound (3′) utilizing standard conditions (ie.butyllithium, at low temperature in a polar aprotic solvent, andfurther, if desired, reacting with MgBr.OEt₂) followed by addition ofthe aldehyde (4) yields the alcohol (5).

[0387] Deprotection of the protected amine of (5) using hydrochloricacid in dioxane gives the amino hydrochloride (6) which is then coupledto the acid (7) by methods available to one skilled in the art to giveintermediate (8). Oxidation using Dess-Martin's Periodinane or othermethods as described in Oxidation in Organic Chemistry by MilosHudlicky, ACS Monograph 186 (1990) yields the ketone (9).

[0388] The final step requires removal of the protecting group from theamine. This may be carried out by a number of methods. For example, onemay utilize aluminum chloride, anisole and nitromethane in a suitablesolvent such as dichloromethane to give the final compound (10).Compound (10) can then be treated with an electrophile (e.g.,methanesulfonyl chloride) with added base to give (14).

[0389] The aldehyde (4) may be prepared via either of three methodsdescribed. The Weinreb amide (12) is prepared from the amino acid (11)which is subsequently reduced to the aldehyde using diisobutylalluminumhydride (DIBAL). Alternatively, one may generate the ester of the aminoacid (13) followed by reduction with DIBAL to afford the aldehyde (4).Further, one may generate the alcohol (13-1) followed by oxidation withSO₃-Py in DMSO.

[0390] The activity of the compounds is presented in FIGS. 23-38 asK_(i) values (nM). K_(i) values were determined, unless otherwiseindicated, essentially as described in WO 96/16080, incorporated hereinby reference.

[0391] Although the compounds described herein and/or their salts may beadministered as the pure chemicals, it is preferable to present theactive ingredient as a pharmaceutical composition. The invention thusfurther provides the use of a pharmaceutical composition comprising oneor more compounds and/or a pharmaceutically acceptable salt thereof,together with one or more-pharmaceutically acceptable carriers thereofand, optionally, other therapeutic and/or prophylactic ingredients. Thecarrier(s) must be ‘acceptable’ in the sense of being compatible withthe other ingredients of the composition and not deleterious to therecipient thereof.

[0392] Pharmaceutical compositions include those suitable for oral orparenteral (including intramuscular, subcutaneous and intravenous)administration. The compositions may, where appropriate, be convenientlypresented in discrete unit dosage forms and may be prepared by any ofthe methods well known in the art of pharmacy. Such methods include thestep of bringing into association the active compound with liquidcarriers, solid matrices, semi-solid carriers, finely divided solidcarriers or combination thereof, and then, if necessary, shaping theproduct into the desired delivery system.

[0393] Pharmaceutical compositions suitable for oral administration maybe presented as discrete unit dosage forms such as hard or soft gelatincapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient; as a powder or as granules; as a solution, asuspension or as an emulsion. The active ingredient may also bepresented as a bolus, electuary or paste. Tablets and capsules for oraladministration may contain conventional excipients such as bindingagents, fillers, lubricants, disintegrants, or wetting agents. Thetablets may be coated according to methods well known in the art., e.g.,with enteric coatings.

[0394] Oral liquid preparations may be in the form of, for example,aqueous or oily suspension, solutions, emulsions, syrups or elixirs, ormay be presented as a dry product for constitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), or preservative.

[0395] The compounds may also be formulated for parenteraladministration (e.g., by injection, for example, bolus injection orcontinuous infusion) and may be presented in unit dose form in ampules,pre-filled syringes, small bolus infusion containers or in multi-doescontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g., sterile, pyrogen- free water, before use.

[0396] For topical administration to the epidermis, the compounds may beformulated as ointments, creams or lotions, or as the active ingredientof a transdermal patch. Suitable transdermal delivery systems aredisclosed, for example, in Fisher et al. (U.S. Pat. No. 4,788,603) orBawas; et al. (U.S. Pat. Nos. 4,931,279, 4,668,504 and 4,713,224).Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents. The active ingredient can also be delivered viaiontophoresis, e.g., as disclosed in U.S. Pat. Nos. 4,140,122, 4383,529,or 4,051,842.

[0397] Compositions suitable for topical administration in the mouthinclude unit dosage forms such as lozenges comprising active ingredientin a flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; mucoadherent gels, and mouthwashescomprising the active ingredient in a suitable liquid carrier.

[0398] When desired, the above-described compositions can be adapted toprovide sustained release of the active ingredient employed, e.g., bycombination thereof with certain hydrophilic polymer matrices, e.g.,comprising natural gels, synthetic polymer gels or mixtures thereof.

[0399] The pharmaceutical compositions according to the invention mayalso contain other adjuvants such as flavorings, coloring, antimicrobialagents, or preservatives.

[0400] It will be further appreciated that the amount of the compound,or an active salt or derivative thereof, required for use in treatmentwill vary not only with the particular salt selected but also with theroute of administration, the nature of the condition being treated andthe age and condition of the patient and will be ultimately at thediscretion of the attendant physician or clinician.

[0401] In general, however, a suitable dose will be in the range of fromabout 0.5 to about 100 mg/kg/day, e.g., from about 1 to about 75 mg/kgof body weight per day, such as 3 to about 50 mg per kilogram bodyweight of the recipient per day, preferably in the range of 6 to 90mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.

[0402] The compound is conveniently administered in unit dosage form;for example, containing 0.5 to 1000 mg, conveniently 5 to 750 mg, mostconveniently, 10 to 500 mg of active ingredient per unit dosage form.

[0403] Ideally, the, active ingredient should be administered to achievepeak plasma concentrations of the active compound of from about 0.5 toabout 75 μM, more preferably, about 1 to 50 μM, most preferably, about 2to about 30 μM. This may be achieved, for example, by the intravenousinjection of a 0.05 to 5% solution of the active ingredient, optionallyin saline, or orally administered as a bolus containing about 0.5-500 mgof the active ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

[0404] The desired dose may conveniently be presented in a single doseor as divided doses administered at appropriate intervals, for example,as two, three, four or more sub-doses per day. The sub-dose itself maybe further divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

[0405] While the invention has been described in connection withspecific embodiments thereof, it will be understood that it is capableof further modifications and this application is intended to cover anyvariations, uses, or adaptations of the invention following, in general,the principles of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth, and as follows in the scopeof the appended claims.

[0406] The following examples are given to illustrate the invention andare not intended to be inclusive in any manner:

EXAMPLES

[0407] The following abbreviations are used below: TFA—trifluoroaceticacid; HOBT—hydroxybenzotriazole; DIEA—diisopropylethylamine;NMM-4—methylmorpholine; DMF—N,N-dimethylformamide; TEA—triethylamine;EDCI—1-(3-dimethylaminopropyl-3-ethylcarbodiimide;BOPCl—bis(2-oxo-3-oxazolidinyl)phosphinic chloride; FMOC—9-fluorenylmethoxycarbonyl; BTD—bicyclic turned dipeptide (see, e.g., Tetrathedron,49:3577-3592 (1993)); THF—tetrahydrofuran

Example 1 (CE-2072)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

[0408] To a mixture containing 0.79 g (5.94 mmol) of N-chlorosuccinimidein 40 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 0.65 ml, (8.85 mmol) of dimethyl sulfide. The reaction was cooledto −25° C. using a carbon tetrachloride/dry ice bath, followed by thedropwise addition of a solution containing(benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]-L-prolinamide (0.90 g,1.49 mmol) in 17 mL of anhydrous toluene. The reaction was allowed tostir for 2 hours at −25° C. followed by the addition of 1.0 mL (7.17mmol) of triethylamine. The cold bath was removed and the mixtureallowed to warin to room temperature and maintained for 20 minutes. Thereaction mixture was diluted with ethyl acetate and washed with water.The organic phase was dried over magnesium sulfate, filtered and thesolvent removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel with 70% ethyl acetate/hexane togive 0.90 g of material which was further purified via preparative HPLCto afford 665 mg (73.9%) of the title compound as a white solid. FAB MS[M+H] m/z; Calcd: 604, Found 604.

[0409] The intermediate(benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]-L-prolinamidewas prepared as follows:

[0410] a. 3-(S)-Amino-2-(RS)-hydroxy-4-methyl Pentanoic Acid.

[0411] To a solution containing3-(S)-[(benzyloxycarbonyl)amino]-2-acetoxy-4-methylpentanenitrile (seeexample 1 of WO 96/16080) (15.2 g, 50.0 mmol) in 183 ml of dioxane wasadded 183 mL of concentrated hydrochloric acid and 7.45 mL of anisole.The reaction mixture was heated to reflux overnight. The hydrolysisreaction was allowed to cool to room temperature and then concentratedin vacuo. The resulting aqueous solution was extracted with ether (2×).The aqueous phase was placed on a Dowex 50X8-100 column (H⁺ form,preeluted with deionized water to pH=7). The column was eluted with 2.0N ammonium hydroxide and the pure fractions concentrated to afford 5.53g (75%) of 3-(S)-amino-2-(R,S)-hydroxy-4-methylpentanoic acid as a paleyellow solid. FAB MS [M+H] m/z; Calcd: 148, Found: 148.

[0412] b. 3-(S) -[(Benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-4-methylpentanoic Acid.

[0413] To a solution under an atmosphere of nitrogen containing 1.0 g(6.8 mmol) of 3-(S)-amino-2-(R,S)-hydroxy-4-methylpentanoic acid in 9.5ml, of 1 N NaOH and 10 mL of dioxane was added 1.43 g (8.4 mmol) ofbenzyl chloroformate. The pH was maintained above pH 8 with 1 N NaOH asneeded. The reaction mixture was allowed to stir at room temperatureovernight. The reaction was diluted with water and washed with ether.The aqueous layer was acidified with 1 N HCl to pH =2 and extracted withether (2×). The combined organic layers were dried over magnesiumsulfate, filtered and evaporated in vacuo to afford 1.75 g (92%) of3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-⁴-methylpentanoic acidas a light yellow viscous oil. FAB MS [M+H] m/z; Calcd: 282, Found: 282.

[0414] c. 3-(S)-[(Benzyloxylcarbonyl)amino]-2-(R,S)-acetoxy-4-methylPentanoic Acid.

[0415] To a solution of3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-4-methylpentanoic acid(1.70 g, 6.04 mmol) and pyridine (4.9 mL) was added acetic anhydride(5.7 mL, 6.17 g, 60.4 mmol) dropwise at room temperature. The reactionwas allowed to stir overnight and was diluted with ethyl acetate andwashed with water (2X). The organic layer was dried over magnesiumsulfate, filtered and evaporated in vacuo to give a thick oil. Theresidue was purified by column chromatography on silica gel with 15%methanol/dichloromethane to afford 1.56 g (80%) of3-(S)-[(benzyloxycarbonyl)amino]-²-(R,S)-acetoxy-4-methyl pentanoic acidas a light yellow viscous oil. FAB MS [M+H] m/z; Calcd: 324, Found: 324.

[0416] d. 1-[(3-Methylphenylacetyl)-2-(2-(R,S)-acetoxy)-3-(S)-[(benzyloxycarbonyl)amino]-4-methylpentanoyl]hydrazine.

[0417] To a solution containing3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-acetoxy-4-methylpentanoic acid(2.3 g, 7.11 mmol) in 40 mL of DMF under a nitrogen atmosphere at 0° C.was added 1.31 g (9.69 mmol) of HOBT and 1.36 g (7.09 mmol) of EDCIAfter stirring for 30 minutes, 1.20 g (7.31 mmol) of 3-methylphenylacetic hydrazide (prepared analogously to the monoacid hydrazides citedby Rabins et. al. (J. Org. Chem, 30:2486 (1965)) and 1.0 mL (9.10 mmol)of NMM were added. The reaction was allowed to warm to room temperatureand stir overnight. The reaction was diluted with ethyl acetate andwashed with 5% potassium hydrogen sulfate, saturated sodium bicarbonate,brine and water. The organic phase was dried over magnesium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel with 10% methanol/dichloromethaneto afford 2.31 g (89.0%) of the title compound as a white solid. FAB MS[M+H] m/z; Calcd: 470, Found: 470.

[0418] e.1-[2-(5-[3-Methylbenzyl)]-1,3,4-oxadiazolyl]-1-acetoxy-2-(S)-[(benzyloxycarbonyl)amino]amino]-3-methylbutane.

[0419] A solution containing 2.31 g (4.92 mmol) of1-[(3-methylphenylacetyl)-2-(2-(R,S)-acetoxy)-3-(S)-[(benzyloxycarbonyl)amino]-4-methylpentanoyl]hydrazine in 25 mL of pyridine and 1.88 g (9.86 mmol) oftoluene sulfonyl chloride was heated at reflux under a nitrogenatmosphere for 72 hours. The solvent was removed under reduced pressureand the residue dissolved in ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel with 5% ethyl acetate/hexane to afford 1.41g (63.5%) of the title compound. FAB MS [M+H] m/z; Calcd: 452, Found:452.

[0420] f1-[2-(5-[3-Methylbenzyl]-1,3,4-oxadiazolyl)]-2-(S)-[(benzyloxycarbonyl)amino]-3-methylbutan-1-ol.

[0421] A solution containing 1.80 g (3.99 mmol) of1-[2-(5-[3-methylbenzyl]-1,3,4-oxadiazolyl)]-1-acetoxy-2-(S)-[(benzyloxycarbonyl)amino]-3-methylbutaneand 0.72 g (5.21 mmol) of potassium carbonate in 30 mL of methanol and 8mL of water was allowed to stir at room temperature for 30 minutes. Thesolvent was removed under reduced pressure and the residue dissolved inethyl acetate and washed with water. The organic phase was dried overmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel with 50%ethyl acetate/hexane to afford 1.46 g (89.3%) of the title compound. FABMS [M+H] m/z; Calcd: 410, Found: 410.

[0422] g.1-[2-(5-[3-Methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-Amino-3-methylbutan-1-olhydrochloride.

[0423] To a solution containing 1.31 g (3.20 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-[(benzyloxycarbonyl)amino]-3-methylbutan-1-olin 25 mL of trifluoroacetic acid under a nitrogen atmosphere at 0° C.was added 0.43 mL (3.94 mmol) of thioanisole. The reaction was allowedto warm to room temperature overnight. The solvent was removed underreduced pressure and the residue dissolved in ether and cooled to −78°C. under a nitrogen atmosphere. To this solution was added 3 mL (3 mmol)of 1 N hydrochloric acid in ether. The resulting white solid was allowedto settle and the ether decanted. Additional ether was added anddecanted (3×). The solid was dried under vacuum to afford 0.92 g (92.2%)of the title compound. FAB MS [M+H) m/z; Calcd: 276, Found: 276.

[0424] h.(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxylmethyl)-2-(S)-methylpropyl]-L-prolinamide.

[0425] To a solution containing 1.30 g (3.38 mmol) of Cbz-Val-Pro-OH in25 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0° C.was added 0.90 g (3.54 mmol) of BOPCl and 0.60 g (3.44 mmol) of DIEA.After stirring for 30 minutes, 0.90 g (2.89 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-ol hydrochloride in 15 mL of dichloromethane and 0.6 mL (3.94mmol) of DIEA was added. The reaction was allowed to stir at 0° C.overnight. The reaction was diluted with dichloromethane and washed witha saturated sodium bicarbonate solution. The organic phase was driedover magnesium sulfate, filtered and evaporated. The residue waspurified by column chromatography on silica gel with 5%methanol/dichloromethane to afford 1.0 g (57.3%) of the title compoundas a tan solid. FAB MS [M+H] m/z; Calcd: 606, Found: 606.

Example 2

[0426](CE-2074)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(methyl)-1,3,4-oxadiazoly]carbony)]-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 FAB MS [M+H] m/z; Calcd: 514, Found: 514.

Example 3

[0427](CE-2075)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3-trifluoromethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1. FAB MS [M+H] m/z; Calcd: 658, Found: 658.

Example 4

[0428] (CE-2100)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(4-Dimethylaminobenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1. FAB MS [M+H] m/z; Calcd: 633, Found: 633.

Example 5

[0429](CE-2124)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(1-napthylenyl)-1,3,4-xadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1. FAB MS [M+H] m/z; Calcd: 640, Found: 640.

Example 6

[0430](CE-2177)(Benzyloxycarbonyl)-L-valyl-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1. FAB MS [M+H] m/z; Calcd: 634, Found: 634.

Example 7

[0431](CE-2178)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,4-methylenedioxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.

[0432] Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z;Calcd: 634, Found: 634.

Example 8

[0433](CE-2052)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-dimethylbenzyl)-1,2,4-oxadiazolyl)carbonyl)-2-(S)-methylpropyl]-L-prolinamide. Prepared similar to Example1 of WO 96/16080. FAB MS [M+H] m/z; Calcd: 618, Found: 618.

Example 9

[0434](CE-2053)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-dimethoxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:650, Found: 650.

Example 10

[0435](CE-2054)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-ditrifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:726, Found: 726.

Example 11

[0436](CE-2055)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:604, Found: 604.

Example 12

[0437](CE-2057)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-biphenylmethine)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:666, Found: 666.

Example 13

[0438](CE-2058)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(4-phenylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:666, Found: 666.

Example 14

[0439](CE-2062)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-phenylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:666, Found: 666.

Example 15

[0440](CE-2066)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-phenoxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:682, Found: 682.

Example 16

[0441](CE-2069)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-cyclohexylmethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:596, Found: 596.

Example 17

[0442](CE-2073)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(α,α-dimethyl-3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:686, Found: 686.

Example 18

[0443](CE-2077)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(1-napthylmethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:640, Found: 640.

Example 19

[0444](CE-2078)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3-pyridylmethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:591, Found: 591.

Example 20

[0445](CE-2096)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(3,5-diphenylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:742, Found: 742.

Example 21

[0446](CE-2115)(Benzyloxycarbonyl)-L-valyl-N-[1-(3-[5-(4-dimethylaminobenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.Prepared similar to Example 1 of WO 96/16080. FAB MS [M+H] m/z; Calcd:633 ), Found: 633.

Example 22

[0447] (CE-2089)2-[5-[(Benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]acetamide.

[0448] To a mixture containing 1.15 g (8.60 mmol) of N-chlorosuccinimidein 43 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 0.95 mL (12.9 mmol) of dimethyl sulfide. The reaction was cooledto −25° C. using a carbon tetrachloride/dry ice bath, followed by thedropwise addition of a solution containing2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-(S)-2-methylpropyl]acetamide(1.52 g, 2.15 mmol) in 15 mL of anhydrous toluene. The reaction wasallowed to stir for 2 hours at −25° C. followed by the addition of 1.2mL (8.60 mmol) of triethylamine. The cold bath was removed and themixture allowed to warm to room temperature over 20 minutes. Thereaction mixture was diluted with ethyl acetate and washed with water.The organic phase was dried over magnesium sulfate, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using a gradient elution of 2 to 10%methanol/dichloromethane to afford 1.19 g of material which was furtherpurified via preparative HPLC to afford 629 mg (41%) of the titlecompound as a white solid. FAB MS [M+H] m/z; Calcd: 707, Found: 707.

[0449] The intermediate2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-(S)-2-methylpropyl]acetamidewas prepared as follows: to a solution containing 1.35 g (3.7 mmol) of1-[3-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride and[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]aceticacid (J. Med. Chem.38:98-108 (1995)) in 10 mL of anhydrous DMF was added1.0 mL (7.44 mmol) of TEA and 0. 76 g (4.94 mmol) of HOBT. The mixturewas cooled to 0° C. and 0.95 g (4.94 mmol) of EDC was added and thereaction mixture was allowed to stir overnight. An additional 1.0 mL(7.44 mmol) of TEA was added and the reaction again allowed to stirovernight. The reaction was diluted with dichloromethane and washed witha saturated ammonium chloride solution (2×) and water. The organic phasewas dried over magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel with 2% methanol/dichloromethane to afford 1.52 g (87%) of the titlecompound. FAB MS [M+H] m/z, Calcd: 709, Found: 709.

Example 23

[0450] (CE-2090)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0451] To a mixture containing 0.41 g (0.56 mmol) of2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(3-[5-(3-trifluormethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]acetamidein 4 mL of trifluoracetic acid at room temperature under a nitrogenatmosphere was added 87 mg (0.70 mmol) of thioanisole. The reactionmixture was allowed to stir for 3 days and. concentrated in vacuo. Theresidue was purified via preparative HPLC to afford 269 mg (47%) of thetitle compound as a white solid. FAB MS [M+H] m/z; Calcd: 573, Found:573.

Example 24

[0452] (CE-2095)2-[5-[(Benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]acetamide.

[0453] To a mixture containing 0.83 g (6.23 mmol) of N-chlorosuccinimidein 32 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 0.7 mL (9.35 mmol) of dimethyl sulfide. The reaction was cooled to−25° C. using a carbon tetrachloride/dry ice bath, followed by thedropwise addition of a solution containing2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-(S)-2-methylpropyl]acetamide(1.02 g, 1.56 mmol) in 12 mL of anhydrous toluene. The reaction wasallowed to stir for 2 hours at −25° C. followed by the addition of 0.9mL (6.23 ) mmol) of triethylamine. The cold bath was removed and themixture allowed to warm to room temperature over 20 minutes. Thereaction mixture was diluted with ethyl acetate and washed with water.The organic phase was dried over magnesium sulfate, filtered andevaporated. The residue was purified by column chromatography on silicagel using 1% methanol/dichloromethane to afford 1.37 g of material whichwas further purified via preparative HPLC to give 368 mg (36%) of thetitle compound as a white solid. FAB MS [M+H] m/z; Calcd: 653, Found:653.

[0454] The intermediate2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-(S)-2-methylpropyl]acetamide was prepared as follows: toa solution containing 1.35 g (3.7 mmol) of1-[2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3-methyl butanehydrochloride and[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]aceticacid (J. Med Chem., 38:98-108 (1995)) in 10 mL of anhydrous DMF wasadded 0.73 mL (6.6 mmol) of NMM and 0.46 g (3.0 mmol) of HOBT. Themixture was cooled to 0° C. and 0.50 g (2.6 mmol) of EDCI was added andthe reaction mixture was allowed to stir for 2 days. The reaction wasdiluted with dichloromethane and washed with a saturated ammoniumchloride solution (2×) and water. The organic phase was dried overmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using agradient elution of 2 to 5% methanol/dichloromethane to afford 1.02 g(77%) of the title compound. FAB MS [M+H] m/z; Calcd: 655, Found: 655.

Example 25

[0455] (CE-2101)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0456] To a mixture containing 0.219 g (0.335 mmol) of2-[5-[(benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(S)-2-methylpropylyl]acetamidein 3 mL of trifluoroacetic acid at room temperature under a nitrogenatmosphere was added 0.05 mL (0.402 mmol) of thioanisole. The reactionmixture was allowed to stir for 3 days and concentrated in vacuo. Theresidue was purified via preoperative HPLC to afford 187 mg (88%) of thetitle compound as a white solid. FAB MS [M+H} m/z; Calcd: 519, Found:519.

Example 26

[0457](CE-2164)(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl-2-(S)-methylpropyl]amide.

[0458] To a mixture containing 1.97 g (14.7 mmol) of N-chlorosuccinimideon 60 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 1.54 mL (21.0 mmol) of dimethyl sulfide. The mixture was allowedto stir for 1 hr. The reaction was cooled to −25° C. using a carbontetrachloride/dry ice bath, followed by the dropwise addition of asolution contain (0.90 g, 1.49 mmol) of(pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)]-2-(S)-methylpropyl]amidein 30 mL of anhydrous toluene. The reaction was allowed to stir for 1hour at −25° C. followed by the addition of 2.16 mL (15.5 mmol) oftriethylamine. The cold bath was removed and the mixture allowed to warmto room temperature over 20 minutes. The reaction mixture was dilutedwith ethyl acetate and washed with water. The organic phase was driedover magnesium sulfate, filtered and evaporated under reduced pressure.The residue was purified by column chromatography on silica gel withethyl acetate/hexane (4:1). The material was further purified viapreparative HPLC to afford 1.20 g (63.4%) of the title compound as awhite solid. FAB MS [M+H] m/z; Calcd: 514, Found: 514.

[0459] The intermediate(pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)]-2-(S)-methylpropyl]amidewas prepared by the following method:

[0460] a. (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl Ester.

[0461] To a suspension containing 3.00 g (27.0 mmol) ofpyrrole-2-carboxylic acid in 75 mL of anhydrous dichloromethane under anitrogen atmosphere at 0° C. was added 6.96 g (27.0 mmol) of BOPCl and14.1 mL (81.0 mmol) of DIEA. After stirring for 30 minutes, 5.97 g (27.0mmol) of N-(benzyl)gylcine-t-butyl ester was added and the reactionallowed to warm to room temperature overnight. The reaction was dilutedwith ethyl acetate and washed with a 5% potassium hydrogensulfate,saturated sodium bicarbonate solution and brine. The organic phase wasdried over magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel using a gradient of 100% hexane to 60% hexane/ethyl acetate toafford 2.92 g (34.4%) of the title compound as a white solid. FAB MS[M+H] m/z Calcd: 315, Found: 315.

[0462] b. (Pyrrole-2-carbonyl)-N-(benzyl)glycine.

[0463] To a solution containing 2.85 g (9.01 mmol) of(Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester in 50 mL ofanhydrous dichloromethane cooled to 0° C. was added 25 mL of TFAdropwise. After 90 minutes an additional 25 mL of TFA was added andallowed to stir for 30 minutes. The mixture was evaporated in vacuo toafford 2.19 g of (Pyrole-2-carbonyl)-N-(benzyl)glycine as a tan solid.FAB MS [M+H] m/z; Calcd. 259, Found 259.

[0464] c.(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[1-(2-[5-(3-methylbenzyl)-],3,4-oxadiazolyl]hydroxymethyl)]-(S)-2-methylpropyl]amide.

[0465] To a solution containing 1.90 g (7.35 mmol) of(Pyrrole-2-carbonyl)-N-(benzyl)glycine in 75 mL of anhydrous DMF wasadded 2.4 mL (22.1 mmol) of NMM and 1.29 g (9.56 mmol) of HOBT. Themixture was cooled to 0° C. and 1.69 g (8.82 mmol) of EDCI was added andthe reaction mixture was allowed to stir. After 30 minutes 2.17 g (6.99mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-ol hydrochloride in 25 mL of anhydrous DMF was added and themixture was allowed to warm to room temperature overnight. The reactionwas diluted with ethyl acetate and washed with 5% potassium hydrogensulfate and water. The organic phase was dried over magnesium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel using a gradient elution of 20 to80% ethyl acetate/hexane to afford 2.02 g (56%) of the title compound.FAB MS [M+H] m/z Calcd: 516, Found: 516.

Example 27

[0466](CE-2097)(Pyrrole-2-carbonyl)-N-(benzyl)glycyl-N-[l-(3-[5-(3-trifluoromethylbenzyl)1-1,2,4-oxadiazolyl]carbonyl)-(S)-methylpropyl]amidewas prepared in a similar manner to Example 25. FAB MS [M+H] m/z; Calcd:568, Found: 568.

Example 28

[0467] (CE-213 0)(2S,5S)-5-Amino-1,2,4,5,6,7-hexahydroazepino-[3,2,1]-indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(R,S)-2-methylpropyl]amide.

[0468] To a solution containing 0.93 g (1.28 mmol) of(2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino [3,2,1]indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]amidein 4.5 mL of anhydrous DMF under an atmosphere of nitrogen was added0.45 mL of diethylamine. After stirring at room temperature for 15 minthe mixture was concentrated under high vacuum. The residue was purifiedvia preparative HPLC to afford 0.57 g (72%) of the title compound as awhite solid. FAB MS [M+H] m/z; Calcd: 502, Found 502.

[0469] The intermediate(2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-[3,2,1]-indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-(S)-2-methylpropyl]amidewas prepared as follows:

[0470] a. (2S, 5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-[3, 2,1]-indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-(S)-2-methylpropyl]amide.

[0471] To a solution containing 1.25 g (2.67 mmol) of(2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino [3,2,1]indole-4-one-carboxylic acid in 200 mL of anhydrous dichloromethane and1 mL of anhydrous DMF under a nitrogen atmosphere at 0° C. was added0.71 g (2.80 mmol) of BOPCl and 0.6 mL (3.45 mmol) of DIEA. Afterstirring for 1 hr 1.14 g (3.66 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of anhydous dichloromethane was added and thereaction mixture allowed to stir at 4° C. overnight. The reaction wasdiluted with dichloromethane and washed with water. The organic phasewas dried over magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by column chromatograph on silica gelusing 3% methanol/dichloromethane to afford 1.30 g (67%) of the titlecompound as tan solid.

[0472] b. (2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-[3,2,1]-indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)]-(S)-2-methylpropyl]amide.

[0473] To a mixture containing 0.95 g (7.16 mmol) of N-chlorosuccinimidein 150 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 0.79 mL (10.7 mmol) of dimethyl sulfide. The mixture was allowedto stir for 30 minutes. The reaction was cooled to −25° C. using acarbon tetrachloride/dry ice bath, followed by the dropwise addition ofa solution containing 1.30 g (1.79 mmol) of(2S,5S)-Fmoc-5-amino-1,2,4,5,6,7-hexahydroazepino-[3,2,1]-indole-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)]-(S)-2-methylpropyl]amidein 10 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at −25° C. followed by the addition of 1.17 mL (8.4 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature over 30 minutes. The reaction mixture wasdiluted with ethyl acetate and washed with water. The organic phase wasdried over magnesium sulfate. The residue was filtered, concentratedunder reduced pressure and purified by column chromatography on silicagel with 10% ethyl acetate/hexane to give 0.93 g (72%) as a tan foam.

Example 29

[0474] (CE-2126)BTD-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.

[0475] To a solution containing 0.41 g (0.59 mmol) ofFMOC-BTD-[I-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazole]carbonyl)-2-(S)-methylpropyl]amidein 4.5 mL of anhydrous DMF under an atmosphere of nitrogen was added 0.5mL of diethylamine. After stirring at room temperature for 30 min themixture concentrated under high vaccum. The residue was purified viapreparative HPLC to afford 0.23 g (66%) of the title compound as a whitesolid. FAB MS [M+H] m/z; Calcd: 472, Found 472.

[0476] The intermediateFmoc-BTD-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amidewas prepared as follows:

[0477] a. (2S, 5S)-Fmoc-BTD-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolylhydroxymethyl)-2-(S)-methylpropyl]amide.

[0478] To a solution containing 1.25 g (2.85 mmol) of FMOC-BTD in 80 mLof anhydrous dichloromethane and 2.5 mL of anhydrous DMF under anitrogen atmosphere at 0° C. was added 0.76 g (2.99 mmol) of BOPC1 and0.6 mL (3.45 mmol) of DIEA. After stirring for 30 minutes and 1.14 g(3.66 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride and 0.6 mL of DIEA in 10 mL of anhydrous dichloromethanewas added and the reaction mixture allowed to stir at 0° C. overnight.The reaction was diluted with dichloromethane and washed with water. Theorganic phase was dried over magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel using 3% methanol/dichloromethane to afford1.13 g (55%) of the title compound as a tan foam.

[0479] b.Fmoc-BTD-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)]-2-(S) -methylpropyl]amide.

[0480] To a mixture containing 0.81 g (6.09 mmol) of N-chlorosuccinimidein 110 mL of 1 :1 anhydrous dichloromethane/toluene at 0° C. under anitrogen atmosphere was added 0.67 mL (9.1 mmol) of dimethyl sulfide.The mixture was allowed to stir for 30 minutes. The reaction was cooledto −25° C. using a carbon tetrachloride/dry ice bath, followed by thedropwise addition of a solution containing 1.06 g (1.52 mmol) ofFmoc-BTD-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]amidein 10 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at −25° C. followed by the addition of 1.0 mL (7.6 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature over 40 minutes. The reaction mixture wasdiluted with ethyl acetate and washed with water. The organic phase wasdried over magnesium sulfate. The resulting mixture was filtered,concentrated under reduced pressure and purified by columnchromatography on silica gel with 70% ethyl acetate/hexane to give 0.53g of the product as a yellow oil. The material was further purified bypreparative HPLC to afford 0.41 g (38.8%) of the title compound as awhite solid.

Example 30

[0481] (CE-2134)(R,S)-3-Amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0482] To a solution containing 0.93 g (1.19 mmol)of(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidein 6.0 mL of anhydrous DMF under an atmosphere of nitrogen was added0.45 mL of diethylamine. After stirring at room temperature for 2.5 hrthe mixture was concentrated under high vaccum. The residue was purifiedvia preparative HPLC to afford 0.030 g (4.5%) of the title compound as awhite solid. FAB MS [M+H] m/z; Calcd: 565, Found 565.

[0483] The intermediate(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared as follows:

[0484] a.(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxym ethyl)-2-(S)-methylpropyl]acetamide.

[0485] To a solution containing 0.75 g (1.41 mmol) of(R,S)-FMOC-3-amino-N-1-carboxymethyl-2-oxo-5-phenyl-1,4,-benzodiazepinein 30 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0°C. was added 0.36 g (1.41 mmol) of BOPC1 and 0.25 mL (1.41 mmol) ofDIEA. After stirring for 1 hr 0.48 g (1.55 mmol) of1-[2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-ol hydrochloride and 0.49 mL (2.82 mmol) of DIEA in 10 mL ofanhydous dichloromethane was added and the reaction mixture allowed tostir at 4° C. overnight. The reaction was diluted with ethyl acetate andwashed with water. The organic phase was dried over magnesium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel using a gradient of 2 to 6%methanol/dichloromethane to afford 1.00 g (89%) of the title compound asa yellow solid.

[0486] b.(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0487] To a mixture containing 0.71 g (7.6 mmol) of N-chlorosuccinimidein 40 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 0.84 ml, (11.4 mmol) of dimethyl sulfide. The reaction was cooledto −25° C. using a carbon tetrachloride/dry ice bath followed by thedropwise addition of a solution containing 1.50 g (1.90 mmol) of(R,S)-FMOC-3-amino-2-oxo-5-phenyl-1,4,-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 10 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at −25° C. followed by the addition of 1.0 mL (7.6 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature over 1 hour. The reaction mixture was dilutedwith ethyl acetate and washed with water. The organic phase was driedover magnesium sulfate. The residue was filtered, concentrated underreduced pressure to afford 0.94 g (62%) of material which was usedwithout further purification. FAB MS [M+H] m/z; Calcd: 787, Found: 787.

Example 31

[0488](CE-2145)(Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.

[0489] To a mixture containing 0.48 g (3.67 mmol) of N-chlorosuccinimidein 30 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 0.40 mL (5.41 mmol) of dimethyl sulfide. After stirring for 1 hrthe reaction mixture was cooled to −25° C. using a carbontetrachloride/dry ice bath followed by the dropwise addition of asolution containing 0.95 g (1.90 mmol) of(benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]amidein 20 mL of anhydrous toluene. The reaction was allowed to stir for 2hours at −25° C. followed by the addition of 0.50 mL (3.6 mmol) oftriethylamine. The cold bath was removed and the mixture was allowed towarm to room temperature. The reaction mixture was diluted withdichloromethane and washed with 1 N HCl (2×), saturated sodiumbicarbonate (2×) and water. The organic phase was dried over magnesiumsulfate. The mixture was filtered and concentrated under reducedpressure to afford 0.61 g. The residue was purified by columnchromatography on silica gel with 50% ethyl acetate/hexane to afford0.27 g of material which was further purified via preparative HPLC toafford 196 mg (33.4%) of the title compound as a white solid. FAB MS[M+H] m/z Calcd: 652, Found 652.

[0490] The intermediate(benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]amidewas prepared by the following procedures:

[0491] a. 2-L-Methyl (2, 3-dihydroindole)carboxylate.

[0492] To a suspension containing 5.00g (30.6 mmol) of2-L-(2,3-dihydroindole)carboxylic acid in 100 mL of anhydrous MeOHcooled to 0° C. was added a slow stream of HCl gas over 20 minutes. Theresulting homogeneous solution was allowed to stir overnight warming toroom temperature. The mixture was evaporated and the residue wascrystallized from methanol/ether to afford, after drying, 5.58 g (85%)of 2-L-methyl (2,3-dihydroindole)carboxylate. b. 2-Methyl[(S)-1-(N-[benzyloxycarbonyl]-L-valyl)-2,3-dihydro-1H-indole]carboxylate.

[0493] To a solution containing 3.00 g (14.0 mmol) of methyl(2,3-dihydroindole)-L-2-carboxylate in 60 mL of anhydrousdichloromethane, under a nitrogen atmosphere at 0° C., 7.15 g (28.8mmol) of BOPC1 and 7.72 mL (70.2 mmol) of DIEA was added a solution of7.06 g (28.08 mmol) of Cbz-Val-OH in 40 mL of anhydrous dichloromethaneand 3 mL of DMF. After stirring for 3 days at 5° C. the mixture wasdiluted with ethyl acetate and washed with 1 N HCl (2×) and brine. Themixture was filtered and evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel using a gradient of9:1 to 1:1 hexane/ethyl acetate to afford 4.85 g (87%) of the titlecompound as a white foam.

[0494] c.2-[(S)-1-(N-[Benzyloxycarbonyl]-L-valyl)-2,3-dihydro-]H-indole]carboxylicAcid.

[0495] To a solution containing 4.85 g (12.17 mmol) of 2-methyl[(S)-1-(N-[benzyloxycarbonyl]-L-valyl)-2,3-dihydro-1H-indole]carboxylatein 45 mL of THF and 15 mL of MeOH at 0° C. was added 15.8 mL of 1 N LiOHdropwise. After 30 minutes 1 N HCl was added to pH 2 and the mixtureextracted with ethyl acetate (3X). The combined organic phases weredried over magnesium sulfate, filtered and evaporated under reducedpresure to afford 4.51 g (93%) of the title compound as a white solid.

[0496] d.(Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]amide.

[0497] To a solution containing 1.09 g (3.96 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-oland 1.31 g (3.3 mmol) of2-[(S)-1-(N-[benzyloxycarbonyl]-L-valyl)-2,3-dihydro-1H-indole]carboxylicacid in 30 mL of anhydrous dichloromethane was added 1.21 mL, (6.93mmol) of DIEA and 0.49 g (3.63 mmol) of HOBT. The mixture was cooled to0° C. and 0.70 g (3.63 mmol) of EDCI was added and the reaction mixturewas allowed to stir overnight. An additional 1.0 mL (7.44 mmol) of TEAwas added and the reaction again allowed to stir overnight. The reactionwas diluted with dichloromethane and washed with 1 N HCl (2×), saturatedsodium bicarbonate (2×) and water. The organic phase was dried overmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel with 80%ethyl acetate/hexane to afford 0.66 g (30%) of the title compound.

Example 32

[0498](CE-2125)(Benzyloxycarbonyl)-L-valyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.Prepared in a similar manner as in Example 30. FAB MS [M+H] m/z; Calcd:706, Found: 706.

Example 33

[0499] (CE-2143)Acetyl-2-L-(2,3-dihydro-1H-indole)-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.Prepared in a similar manner as in Example 30. FAB MS [M+H] m/z; Calcd:515, Found: 515.

Example 34

[0500] (CE-2165)N-Acetyl-2-(L)-(2,3-dihydro-1H-indole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]amide.Prepared in a similar manner as in Example 30. FAB MS [M+H] m/z; Calcd:461; Found: 461.

Example 35

[0501](CE-2104)(Morpholino-N-carbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.

[0502] To a mixture containing 0.69 g (5.17 mmol) of N-chlorosuccinimidein 60 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 0.60 mL (8.17 mmol) of dimethyl sulfide. The reaction was cooledto −25° C. using a carbon tetrachloride/ dry ice bath, followed by theaddition of a solution containing(morpholino-N-carbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S-)methylpropyl]-L-prolinamide (0.75 g, 1.28 mmol) in 10 mL of anhydrous toluene.The reaction was allowed to stir for 2 hours at −25° C. followed by theaddition of 1.1 mL (0.83 g, 7,89 mmol) of triethylamine. The cold bathwas removed and the reaction was allowed to warm to room temperatureover 20 minutes. The reaction was diluted with ethyl acetate and washedwith water. The organic phase was dried over magnesium sulfate andfiltered. The solvents were evaporated in vacuo and the residue purifiedby column chromatography, 70% ethyl acetate/hexane on silica gel. Finalpurification was performed by preparative HPLC to afford 405 mg (54.3%)of the title compound as a white solid. FAB MS [M+H] m/z; Calcd: 583,Found: 583.

[0503] The intermediate(Morpholino-N-carbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyll)-2-(S)-methylpropyl]-L-prolinamidewas prepared as follows:

[0504] a. (Morpholino-N-carbonyl)-L-valyl-L-proline-O-t-butyl ester.

[0505] To a solution containing L-valyl-L-proline-O-t-butyl-ester (1.80g, 5.87 mmol) in 80 mL of anhydrous methylene chloride and 1.5 mL (13.64mmol) of N-methyl morpholine under a nitrogen atmosphere at 0° C. wasadded morpholine carbonyl chloride dropwise. The mixture was allowed towarm to room temperature overnight. The reaction was diluted withmethylene chloride and washed with water. The organic layer was driedover magnesium sulfate, filtered and evaporated. The residue waspurified by column chromatography on silica gel with 10%methanol/dichloromethane to afford 1.98 g (88%) of the title compound asa white solid. FAB MS [M+H] m/z; Calcd: 384, Found 384.

[0506] b. (Morpholino-N-carbonyl)-L-valyl-L-proline.

[0507] To a solution containing(morpholino-N-carbonyl)-L-valyl-L-proline-O-t-butyl ester (2.0 g, 5.22mmol) in 80 mL of anhydrous methylene chloride under a nitrogenatmosphere at 0° C. was added trifluoroacetic acid (13 mL, 130 mmol).The mixture was allowed to warm to room temperature overnight and thesolvents were evaporated in vacuo to give 2.26g of a viscous oil. Thematerial was used without further purification.

[0508] c. (Morpholino-N-carbonyl)-L-valyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]-L-prolinamide.

[0509] To a solution containing 0.95 g (2.90 mmol) of(morpholino-N-carbonyl)-L-valyl-Proline in 25 mL of anhydrousdichloromethane under a nitrogen atmosphere at 0° C. was added 0.80 g(3.14 mmol) of BOPCI and 1.5 mL (8.61 mmol) of DIEA. After 30 minutes,0.75g (2.41 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 1.1 mL (6.31 mmol) of DIEAwere added. The reaction was allowed to stir at 0° C. overnight. Thereaction was diluted with dichloromethane and washed with a saturatedNaHCO₃ solution. The organic phase was dried over magnesium sulfate andfiltered. The mixture was concentrated in vacuo and the residue purifiedby column chromatography on silica gel using 6% methanol/dichloromethaneto afford 0.77 g (54.84%) of the title compound as a white solid. FAB MS[M+H] m/z; Calcd: 585, Found: 585.

Example 36

[0510] (CE-2079)3-(S)-[(Benzyloxycarbonyl)amino]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0511] To a mixture containing 2.37 g (17.75 mmol) ofN-chlorosuccinimide in 100 mL of anhydrous toluene at 0° C. under anitrogen atmosphere was added 1.94 mL (2.64 mmol) of dimethyl sulfide.The reaction was cooled to −25° C. using a carbon tetrachloride/dry icebath, followed by the dropwise addition of a solution containing 2.5 g(4.44 mmol) of3-(S)-[(benzyloxycarbonyl)amino]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide in 20 mL of anhydrous toluene. Upon complete addition,the reaction was allowed to stir at −25° C. for 2 hours, followed by theaddition of 3.0 mL (21.52 mmol) of triethylamine. The cold bath wasremoved and the reaction warmed to room temperature and stirred for 30minutes. The reaction was diluted with ethyl acetate and washed withwater. The organic phase was dried over magnesium sulfate. Filtration,removal of solvent and column chromatography of the residue on silicagel with 5% methanol/dichloromethane afforded 1.8 g of a pale yellowsolid. Subsequent preparative HPLC gave 950 mg (38.1%) of the titlecompound as a white solid. FAB MS [M+H] m/z; Calcd: 562, Found: 562.

[0512] The intermediate3-(S)-[(benzyloxycarbonyl)amino]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide was prepared as follows:

[0513] a. 3-(S)-[(Benzyloxycarbonyl)amino]—lactam.

[0514] To a mixture containing 9.9 g (37.18 mmol) of Cbz-ornithine in150 mL of acetonitrile under a nitrogen atmosphere was added 78 mL(369.70 mmol) of hexamethyldisilazane. The reaction was heated at refluxfor 48 hours. The reaction mixture was cooled to room temperature andpoured into 250 mL of cold methanol. The solvent was removed underreduced pressure. Chloroform was added and the mixture filtered througha plug of celite. The filtrate was concentrated under reduced pressureand the residue dissolved in ethyl acetate. Hexane was added until thesolution was slightly turbid and then allowed to stand overnight. Theresultant solid was filtered and dried to afford 8.37 g (90.7%) of thetitle compound.

[0515] b. N-[3-(S)-(Benzyloxycarbonyl)amino]-ε-lactam-t-butyl acetate.

[0516] To a solution containing 1.0 g (4.03 mmol) of3-(S)-[(benzyloxylcarbonyl)amino]-ε-lactam in 20 mL of anhydrous DMFunder a nitrogen atmosphere was added 1.50 mL (10.16 mmol) ofbromo-t-butyl acetate and 1.17 g (5.05 mmol) of silver oxide. Thereaction was heated to 45° C. for 5 hours, diluted with acetonitrile andfiltered through a pad of celite. The filtrate was concentrated underreduced pressure and the residue dissolved in ethyl acetate and washedwith water. The organic phase was dried over magnesium sulfate.Filtration, removal of solvent and column chromatography of the residueon silica get with 60% ethyl acetate/hexane afforded 1.18 g (80.79%) ofthe title compound. FAB MS [M+H] m/z; Calcd: 363, Found: 363.

[0517] c. N-[3-(S)-(Benzyloxycarbonyl)amino)-ε-lactam-carboxymethane.

[0518] To a solution containing 0.55 g (1.52 mmol) ofN-[3-(S)-(Benzyloxy carbonyl)amino]-ε-lactam-t-butyl acetate in 20 mL(15.58 mmol) of trifluoroacetic acid. The reaction was allowed to warmto room temperature overnight. The solvent was removed under reducedpressure. The residue was dissolved in ether acetate and washed withwater. The organic phase was dried over magnesium sulfate. Filtrationand removal of solvent afforded 0.50 of the title compound. FAB MS [M+H]m/z; Calcd: 307, Found: 307.

[0519] d.3-(S)-[(Benzyloxycarbonyl)amino]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

[0520] To a solution containing 2.72 g (8.88 mmol) ofN-[3-(S)-(Benzyloxycarbonyl)amino]-ε-lactam-carboxymethane in 80 ml ofdichloromethane under a nitrogen atmosphere at 0° C. was added 2.37 g(9.31 mmol) of BOPCI and 1.60 mL (9.91 mmol) of DIEA. The reacton wasallowed to stir at 0° C. for 30 minutes followed by the addition of 2.37g (7.60 mmol) of1-[3-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3methylbutan-1-ol hydrochloride in 20 mL of dichloromethane and 1.60 mL (9.19mmol) of DIEA. The reaction was allowed to stir at 0° C. overnight. Thereaction was diluted with dichloromethane and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration, removal ofsolvent and column chromatography of the residue on silica get with 10%methanol/dichloromethane afforded 2.58 g (50.23%) of the title compound.FAB MS [M+H] m/z; Calcd: 564, Found: 564.

Example 37

[0521] (CE-2080) 3-(S)-Amino-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidetrifluoroacetic acid salt.

[0522] This compound was prepared via deprotection of3-(S)-[benzyloxycarbonyl)amino)-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide under standard conditions to one skilled in the art toafford the title compound. FAB MS [M+H] m/z; Calcd: 428, Found: 428.

Example 38

[0523] (CE-2091) 3-(S)-[(4-Morpholinocarbonyl-butanoyl)amino]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.

[0524] To a solution containing 0.089 g (0.475 mmol) of 4-morpholinocarbonyl butanoic acid in 10 mL of dichloromethane under a nitrogenatmosphere at 0° C. was added 0.127 g (0.498 mmol) of BOPCI and 0.09 mL(0.492 mmol) of DIEA. The reaction was allowed to stir for 30 minutesfollowed by the addition of 0.22 g (0.406 mmol) of3-(S)-amino-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methyl propyl]acetamidetrifluoroacetic acid salt. The reaction was allowed to stir at 0° C.overnight. The reaction was diluted with dichloromethane and washed withwater. The organic phase was dried over magnesium sulfate. Filtration,removal of solvent and purification via preparative HPLC afforded 0.044g (18%) of the title compound. FAB MS [M+H] m/z; Calcd: 597, Found: 597.

Example 39

[0525] (CE-2087)6-[4-Fluorophenyl]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0526] To a mixture containing 0.70 g (5.24 mmol) andN-chlorosuccinimide in 30 mL of anhydrous toluene at 0° C. under anitrogen atmosphere was added 0.60 mL (8.17 mmol) of dimethyl sulfide.The reaction was cooled to −25° C. using a carbon tetrachloride/dry icebath, followed by the dropwise addition of a solution containing 0.67 g(1.32 mmol) of 6-[4-fluorophenyl]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide in15 mL of anhydrous toluene. Upon complete addition, the reaction wasallowed to stir at −25° C. for 2 hours followed by the addition of 0.90mL (6.46 mmol) of triethylamine. The cold bath was removed and thereaction allowed to warm to room temperature and maintained for 20 min.The reaction was diluted with ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration, removal ofsolvent under reduced pressure and column chromotography of the residueon silica gel with 10% methanol/dichloromethane afforded 0.61 g of apale yellow solid. Subsequent preparative HPLC gave 338 mg (50.5%) ofthe title compound. FAB MS [M+H] m/z; Calcd: 507, Found: 507.

[0527] The intermediate6-[4-fluorophenyl]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidewas prepared as follows:

[0528] a. 6-[4-Fluorophenyl]-ε-carboxymethylene-2-piperidinone.

[0529] To a solution containing 2.15 g (8.11 mmol) of6-[4-fluorophenyl]-1-carbomethoxymethylene-2-piperidinone, prepared in asimilar fashion to that reported by Compernolle (Tetrahedron, 49:3193(1993)) in 70 mL of methanol and 20 mL of water under a nitrogenatmosphere was added 0.55 g (13.11 mmol) of lithium hydroxide. Thereaction was allowed to stir at room temperature for 2 hours. Thesolvent was removed under reduced pressure. The residue was diluted withwater and washed with ethyl acetate. The aqueous phase was acidifiedwith 1 N hydrochloric acid and extracted with ethyl acetate. The organicphase was dried over magnesium sulfate. Filtration and removal ofsolvent afforded 2.0 g (98.2%) of the title compound. FAB MS [M+H] m/z;Calcd: 252, Found: 252.

[0530] b.6-[4-Fluorophenyl]-ε-lactam-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

[0531] To a solution containing 1.04 g (4.14 mmol) of6-[4-fluorophenyl]-6-carboxymethylene-2-piperidinone in 25 mL ofanhydrous dichloromethane under a nitrogen atmosphere at 0° C. was added1.10 g (4.32 mmol) of BOPCI and 0.80 mL (4.59 mmol) of DIEA. Afterstirring for 30 minutes, a solution containing 1.1 g (3.53 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 1.10 mL (6.31 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight. The reactionwas diluted with dichloromethane and washed with a saturated sodiumbicarbonate solution. The organic phase was dried over magnesiumsulfate. Filtration, removal of solvent under reduced pressure andcolumn chromatography of the residue on silica gel with 10%methanol/dichloromethane afforded 736 mg (41.0%) of the title compound.FAB MS [M+H] m/z; Calcd: 509, Found: 509.

Example 40

[0532] (CE-2121)2-[2-(R,S)-Phenyl-4-oxothiazolidin-3-yl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0533] To a mixture containing 2.05 g (15.38 mmol) ofN-chlorosuccinimide in 250 mL of anhydrous toluene at 0° C. under anitrogen atmosphere was added 1.70 mL (23.06 mmol) of dimethyl sulfide.The reaction was cooled to −25° C. using a carbon tetrachloride/dry icebath, followed by the addition of 1.90 g (3.84 mmol) of2-[2-(R,S)-phenyl-4-oxothiazolidin-3-yl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 20 mL of anhydrous toluene dropwise. The reaction was allowed to stirat −25° C. for 2 hours, followed by the addition of 2.52 mL (18.07 mmol)of triethylamine. The cold bath was removed and the reaction allowed towarm to room temperature over 40 minutes. The reaction was diluted withethyl acetate and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent and columnchromatography of the residue on silica gel with 60% ethylacetate/hexane afforded 1.10 g of a yellow oil. This was furtherpurified via preparative HPLC to give 0.45 g (24%) of the title compoundas an off-white solid. FAB MS [M+H] m/z; Calcd: 493, Found 493.

[0534] The intermediate2-[2-(R,S)-phenyl-4-oxothiazolidin-3-yl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methypropyl]acetamidewas prepared as follows: to a solution containing 1.78 g (7.51 mmol) of2-(2-phenyl-4-oxothiazolidin-3-yl) acetic acid, prepared according toHolmes (J Org. Chem, 60:7328 (1995)), in 80 mL of dichloromethane undera nitrogen atmosphere at 0° C. was added 2.04 g (8.02 mmol) of BOPCI and1.35 mL (7.76 mmol) of DIEA. After stirring for 30 minutes, 2.0 g (6.41mmol) of1-[3-[5-(3-methylbenzyl)]-1,3,4-oxadiazolyl]-2-(S)-amino-3-methyl-butan-1-olhydrochloride in 50 mL of dichloromethane and 1.35 mL (7.76 mmol) ofDIEA was added. The reaction was allowed to stir at 0° C. overnight. Thereaction mixture was diluted with dichloromethane and washed with water.The organic phase was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. Column chromatography of theresidue on silica gel with 4% methanol/dichloromethane afforded 2.30 gof a yellow foam. Subsequent preparative HPLC gave 1.9 g of the titlecompound. FAB MS [M+H] m/z; Calcd: 495, Found: 495.

Example 41

[0535] (CE-2122)2-[2-(R,S)-Benzyl-4-oxothiazolidin-3-yl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner as in Example 39. FAB MS [M+H] m/z;Calcd: 507, Found: 507.

Example 42

[0536] (CE-2136) 2-[(2-(R,S)-Benzyl-4-oxothiazolidin-3-yloxide]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S,)-methylpropyl]acetamide.

[0537] To a solution containing 1.31 g (2.59 mmol) of2-[2-(R,S)-benzyl-4-oxothiazolidin-3-yl)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-acetamide in 15 mL of methanol under a nitrogen atmosphere wasadded 0.51 mL (5.17 mmol) of 30% hydrogen peroxide. The reaction wasallowed to stir at room temperature overnight and then partitionedbetween brine and dichloromethane. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel with 85% ethylacetate/hexane afforded 0.73 g of a tan oil. Subsequent preparative HPLCgave 0.54 g (48%) of the title compound. FAB MS [M+H] m/z; Calcd: 523,Found 523.

Example 43

[0538] (CE-2137) 2-[2-(R,S)-Benzyl-4-oxothiazolidin-3-yloxide]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(R,S,)-methylpropyl]acetamide.Prepared in a similar manner as in Example 41. FAB MS [M+H] m/z; Calcd:577, Found 577.

Example 44

[0539] (CE-2118)2-[2-(R,S)-Phenyl-4-oxometathiazan-3-yl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as in Example 39. FAB MS [M+H] m/z; Calcd:507, Found: 507.

Example 45

[0540](CE-2140)(1-Benzoyl-3,8-quinazolinedione)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0541] To a mixture containing 1.70 g (2.74 mmol) of N-chlorosuccinimidein 75 ml, of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 1.70 ml, (23.15 mmol) of dimethyl sulfide. The reaction was cooledto −25° C. using a carbon tetrachloride/dry ice bath, followed by theaddition of 1.90 g (3.27 mmol) of(1-Benzoyl-3,8-quinazolinedione)-N-[1(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide in 10 mL of toluene dropwise. The reaction was allowedto stir at −25° C. for 2 hours, followed by the addition of 3.20 ml,(22.96 mmol) of triethylamine. The cold bath was removed and thereaction allowed to warm to room temperature and maintained for 15minutes. The reaction was diluted with ethyl acetate and washed withwater. The organic phase was dried over magnesium sulfate, filtered, andthe solvent removed under reduced pressure. The residue waschromatographed on silica gel with 5% methanol/dichloromethane to afford1.37 g of a brown oil. This was further purified via preparative HPLC togive 450 mg (40.1%) of the title compound. FAB MS [M+H] m/z; Calcd: 580,Found: 580.

[0542] The intermediate(1-benzoyl-3,8-quinazolinedione)-N-[1-(2-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidewas prepared as follows:

[0543] a. 1-Benzoyl-3,8-quinazolinedione-2-t-butyl Acetate.

[0544] To a solution containing 5.0 g (18.78 mmol) of1-Benzoyl-3,8-quinazolinidione prepared in a similar manner to thatreported by Melnyk et al. (Tetrahedron Lett., 37:4145 (1996)), in 100 mLof DMF under a nitrogen atmosphere was added 4.30 mL (29.12 mmol) ofbromo t-butylacetate and 5.4 g (23.30 mmol) of silver oxide. Thereaction was heated to 50° C. overnight, diluted with ethyl acetate andwashed with water. The organic phase was dried over magnesium sulfate.Filtration, removal of solvent under reduced pressure and columnchromatography of the residue on silica gel with 40% ethylacetate/hexane gave 5.25 g (73.49%) of product. FAB MS [M+H] m/z; Calcd:381, Found:381.

[0545] b. 1-Benzoyl-2-carboxymethylene-3,8-quinazolinedione.

[0546] To a solution containing 5.20 g (13.67 mmol) of1-benzoyl-3,8-quinazolinedione-2-t-butyl acetate in 300 mL ofdichloromethane under a nitrogen atmosphere at 0° C. was added 21.0 mL(211.44 mmol) of trifluroacetic acid. The reaction was allowed to warmto room temperature overnight. The solvent was removed under reducedpressure and the residue dissolved in ethyl acetate and washed withwater. The organic phase was dried over magnesium sulfate. Filtrationand removal of solvent afforded 4.32 g (97.45%) of the title compound.FAB MS [M+H]m/z; Calcd: 325, Found: 325.

[0547] c.(1-Benzoyl-3,8-quinazolinedione)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl/acetamide.

[0548] To a solution containing 1.80 g (5.55 mmol) of1-benzoyl-2-carboxymethylene-3,8-quinazolinedione in 100 mL of anhydrousdichloromethane and 5 mL of DMF under a nitrogen atmosphere at 0° C. wasadded 1.90 g (7.46 mmol) of BOPCI and 1.40 mL (8.05 mmol) of DIEA. Afterstirring for 30 minutes, a solution containing 1.70 g (5.45 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 20 mL of dichloromethane and 3.80 mL (21.84 mmol) ofDIEA was added. The reaction was allowed to stir at 0° C. overnight,diluted with dichloromethane and washed with water. The organic phasewas dried over magnesium sulfate. Filtration, removal of solvent underreduced pressure and column chromatography of the residue on silica gelwith 10% methanol/dichloromethane afforded 1.93 g (60.9%) of the titlecompound. FAB MS[M+H]m/z; Calcd: 582, Found: 582.

Example 46

[0549](CE-2138)(1-Benzoyl-3,6-piperazinedione)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as in Example 44. FAB MS [M+H]m/z; Calcd:532, Found: 532.

Example 47

[0550](CE-2147)(1-Phenyl-3,6-piperazinedione)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)2-(S)-methylpropyl]acetamide.Prepared in a similar manner as in Example 44. FAB MS [M+H]m/z; Calcd:504, Found: 504.

Example 48

[0551](CE-2148)(1-Phenyl-3,6-piperazinedione)-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as in Example 44. FAB MS [M+H] m/z;Calcd:558, Found: 558.

Example 49

[0552] (CE-2108)3-[(Benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0553] To a mixture containing 0.16 g (1.18 mmol) of N-chlorosuccinimidein 20 mL of anhydrous toluene at 0° C. under a nitrogen atmosphere wasadded 0.13 mL (1.77 mmol) of dimethyl sulfide. The reaction was cooledto −25° C. using a carbon tetrachloride/dry ice bath followed by theaddition of a solution containing 0.18 g (0.30 mmol) of3-[(benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-Oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 20 mL of methylene chloride dropwise. The reaction was allowed tostir at −25° C. for 2 hours, followed by the addition of 0.19 mL (1.38mmol) of triethylamine. The cold bath was removed and the reaction wasallowed to warm to room temperature and maintained for 30 minutes. Thereaction was diluted with ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate. Filtration, removal ofsolvent under reduced pressure and column chromatography of the residueon silica gel with 3% methanol/dichloromethane afforded 0.23 g of anoil. Further purification via preparative HPLC gave 100 mg of the titlecompound.

[0554] FAB MS [M+H} m/z; Calcd: 608, Found: 608

[0555] The intermediate3-[(benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethly)-2-(S)-methylpropyl]acetamidewas prepared as follows:

[0556] a. 3-[(Benzyloxycarbonyl)amino]-quinoline-2-one.

[0557] To a solution containing 0.5 g (3.10 mmol) of3-amino-quinoline-2-(1H)-one described by Anderson, et. al. (J.Heterocyclic Chem., 30:1533 (1993)) in 40 mL, of dioxane under anitrogen atmosphere was added 0.14 g (3.4 mmol) of sodium hydroxide in14 ml, of water. The reaction mixture was cooled to 0° C., followed bythe addition of 0.50 mL (3.4 mmol) of benzylchloroformate. The pH of thereaction was maintained above 8.0 with additional 1 N sodium hydroxide.The reaction was allowed to warm to room temperature and stirred for 2hours. The reaction was diluted with methylene chloride and washed withwater. The organic phase was dried over magnesium sulfate. Filtration,removal of solvent under reduced pressure and column chromatography ofthe residue on silica gel with 2% methanol/dichloromethane afforded 0.32g (35%) of product as a white solid. FAB MS [M+H] m/z; Calcd: 295,Found: 295

[0558] b.3-[(Benzyloxycarbonyl)amino]-quinoline-2-one-N-t-butyl-acetate.

[0559] To a solution containing 0.30 g (1.02 mmol) of3-[(benzyloxycarbonyl)amino]-quinoline-2-one in 20 mL of DMF under anitrogen atmosphere was added 0.15 mL (1.02 mmol) of t-butylbromoacetate and 0.24 g (1.02 mmol) of silver oxide. The reaction washeated to 70° C. and maintained overnight. The reaction mixture wasdiluted with acetonitrile and filtered through a pad of celite. Thefiltrate was concentrated under reduced pressure and the residuepartitioned between ethyl acetate and water. The organic phase was driedover magnesium sulfate. Filtration, removal of solvent under reducedpressure and column chromatography of the residue on silica gel withdichloromethane afforded 0.20 g (48%) or product as a white solid. FABMS [M+H] m/z; Calcd: 409, Found: 409.

[0560] c.3-[(Benzyloxycarbonyl)amino]-1-carboxymethylene-quinoline-2-one.

[0561] To a solution containing 1.30 g (3.18 mmol) of3-[(benzyloxycarbonyl)amino]-quinoline-2-one-N-t-butyl-acetate in 35 mLof dichloromethane under a nitrogen atmosphere at 0° C. was added 2.45mL (31.84 mmol) of trifluoroacetic acid. The reaction was allowed towarm to room temperature overnight. The solvent was removed underreduced pressure to afford 1.09 g (97%) of the title compound. FAB MS[M+H] m/z; Calcd: 353, Found. 353

[0562] d.3-[(Benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

[0563] To a solution containing 1.09 g (3.09 mmol) of3-[(benzyloxycarbonyl)aminol-1-carboxymethylene-quinoline-2-one in 50 mLof anhydrous dichloromethane and 3 mL of DMF under a nitrogen atmosphereat 0° C. was added 0.84 (3.31 mmol) of BOPCI and 1. 10 mL (6.31 mmol) ofDIEA. After stirring for 30 minutes, 0.82 g (2.65 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2(S)-amino-3-methylbutan-1-olhydrochloride in 8 mL of dichloromethane and 0.56 mL (3.20 mmol) of DIEAwas added. The reaction was allowed to stir at 0° C. overnight, dilutedwith dichloromethane and washed with water. The organic phase was driedover magnesium sulfate. Filtration, removal of solvent under reducedpressure and column chromatography of the residue on silica gel with 5%methanol/dichloromethane afforded 0.37 g (30.3%) of product. FAB MS[M+H] m/z; Calcd: 610,Found:610

Example 50

[0564] (CE-2107)3-[(Benzyloxycarbonyl)amino]-7-piperidinyl-quinoline-2-one-N-[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 48. FAB MS [M+H] m/z;Calcd: 691, Found: 691

Example 51

[0565] (CE-2117)3-Carbomethoxy-4-fluoro-quinoline-2-one-N-[1-(2-[5-(3-methybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 48. FAB MS [M+H] m/z;Calcd: 535, Found: 535

Example 52

[0566] (CE-2113)3-(Amino-quinoline-2-one)-N[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0567] To a solution containing 2.30 g (3.79 mmol) of3-[(benzyloxycarbonyl)amino]-quinoline-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]-carbonyl)-2-(S)-methyl propyl]acetamide in 60mL of trifluoroacetic acid under a nitrogen atmosphere at 0° C. wasadded 0.53 mL (4.54 mmol) of thioanisole. The reaction was allowed towarm to room temperature overnight. The solvent was removed underreduced pressure. Subsequent preparative HPLC afforded 0.61 g (27%) ofthe title compound. FAB MS [M+H] m/z; Calcd: 474, Found: 474

Example 53

[0568] (CE-2116)3-[(4-Morpholino)aceto]amino-quinoline-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0569] To a solution containing 0.32 g (1.22 mmol) of 4-morpholinoacetic acid in 18 mL of dichloromethane under a nitrogen atmosphere at0° C. was added 0.33 g (1.30 mmol) of BOPCI and 0.22 mL (1.26 mmol) ofDIEA. After stirring for 1.5 hours, a solution containing 0.61 g (1.04mmol) of3-(amino-quinoline-2-one)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methypropyl]acetamidein 20 mL of dichloromethane was added followed by 0.22 mL (1.26 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight, diluted withdichloromethane and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand preparative HPLC afforded 0.20 g (27%) of the title compound. FAB MS[M+H] m/z; Calcd: 602, Found: 602

Example 54

[0570] (CE-2088)3,4-Dihydro-quinoline-2-one-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-N-methylpropyl]acetamidefrom commercially available 3,4-Dihydro-2(1H)-quinoline-2-one. Preparedin a similar manner as shown in Example 52. FAB MS [M+H] m/z; Calcd:461, Found: 461

Example 55

[0571] (CE-2099) 1-Acetyl-3-benzylidenepiperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0572] To a solution containing 0.55 g (4.15 mmol) ofN-chlorosuccinimide in 35 mL of anhydrous toluene at 0° C. under anitrogen atmosphere was added 0.46 mL (6.22 mmol) of dimethyl sulfide.The reaction was cooled to −25° C. using a carbon tetrachloride/dry icebath, followed by the addition of a solution containing 0.58 g (1.04mmol) of 1-acetyl-3-benzylidenepiperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 8 mL of toluene. The reaction was allowed to stir at −25° C. for 2 h,followed by the addition of 0.68 mL (4.87 mmol) of triethylamine. Thecold bath was removed and the reaction allowed to warm to roomtemperature and maintained for 40 minutes. The reaction was partitionedbetween ethyl acetate and water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel 60% ethylacetate/hexane gave 0.54 g of a brown oil which was further purified viapreparative HPLC to give 146 mg (25%) of the title compound. FAB MS[M+H] m/z; Calcd: 558, Found: 558

[0573] The intermediate 1-acetyl-3-benzylidenepiperazine-2,5-dione-N[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidewas prepared as follows:

[0574] a. 1-A cetyl-3-benzylidene piperazine-2,5-dione-N-t-butylAcetate.

[0575] To a solution containing 6.36 g (26.00 mmol) of1-Acetyl-3-benzylidene piperazine-2,5-dione described by D. Villemn, etal. (Synthetic Communications, 20:3325 (1990)), in 100 mL of DMF under anitrogen atmosphere was added 9.62 mL (65.1 0 mmol) of t-butylbromoacetate and 7.55 g (32.60 mmol) of silver oxide. The reaction washeated to 45° C. overnight. The reaction was filtered through a plug ofcelite and the filtrate concentrated under reduced pressure. The residuewas diluted with ethyl acetate and washed with water. The organic phasewas dried over magnesium sulfate. Filtration, removal of solvent underreduced pressure and column chromatography of the residue on silica gelwith 1% methanol/dichloromethane gave 5.37 g of a tan solid. Furtherpurification via preparative HPLC gave 2.5 g (27%) of the titlecompound. FAB MS[M+H]m/z; Calcd: 359, Found: 359.

[0576] b.1-Acetyl-3-benzylidene-4-carboxymethylene-piperazine-2,5-dione.

[0577] To a solution containing 2.50 g (6.98 mmol) of1-acetyl-3-benzylidene piperazine-2,5-dione-N-t-butyl acetate in 100 mLof dichloromethane under a nitrogen atmosphere at 0° C. was added 5.40mL (69.80 mmol) of trifluoroacetic acid. The reaction was allowed towarm to room temperature overnight. The solvent was removed underreduced pressure and the residue diluted with ethyl acetate and washedwith a saturated sodium bicarbonate solution. The aqueous phase wasacidified with 1 N hydrochloric acid and extracted with ethyl acetate.The organic phase was dried over magnesium sulfate. Filtration andremoval of solvent under reduced pressure gave 1.96 g (96%) of productas a tan solid. FAB MS [M+H] m/z; Calcd: 303, Found: 303.

[0578] c. 1-Acetyl-3-benzylidenepiperazine-2,5-dione-N-[1-(2[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

[0579] To a solution containing 0.65 g (2.14 mmol) of1-acetyl-3-benzylidene-4-carboxymethylene-piperazine-2,5-dione in 40 mLof anhydrous dichloromethane and 3 mL of DMF under a nitrogen atmosphereat 0° C. was added 0.57 g (2.24 mmol of BOPCI and 0.39 mL (2.21 mmol) ofDIEA. After stirring for 30 minutes, a solution containing 0.57 g (1.83mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 0.39 mL (2.21 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight, diluted withdichloromethane and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel with 5%methanol/dichloromethane gave 0.13 g (58%) of product. FAB MS[M+H] m/z;Calcd: 560, Found: 560.

Example 56

[0580] (CE-2105) 1-Acetyl-3-(4-fluorobenzylidene)piperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 54. FAB MS[M+H] m/z;Calcd: 576, Found:576.

Example 57

[0581] (CE-2111) 1-Acetyl-3-(4-dimethylamino benzylidene)piperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 54. FAB MS[M+H] m/z;Calcd: 601, Found: 601.

Example 58

[0582] (CE-2112) 1-Acetyl-3-(4-carbomethoxy benzylidene)piperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 54. FAB MS[M+H] m/z;Calcd: 616, Found: 616.

Example 59

[0583] (CE-2114) 1-Acetyl-3-[(4-pyridyl)methylene]piperazine-2,5-dione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 54. FAB MS[M+H] m/z;Calcd: 559, Found: 559.

Example 60

[0584] (CE-2144)4-[1-Benzyl-3-(R)-benzyl-piperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0585] To a mixture containing 2.20 g (16.48 mmol) ofN-chlorosuccinimide in 100 ml, of anhydrous toluene under a nitrogenatmosphere at 0° C. was added 2.1 ml, (28.59 mmol) of dimethyl sulfide.The reaction was cooled to −25° C. using a carbon tetrachloride/dry icebath, followed by the addition of a solution containing 2.5 g (4.10mmol) of 4-[1-benzyl-3-(R)-benzylpiperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 15 mL of toluene. The reaction was allowed to stir at −25° C. for 2hours, followed by the addition of 4.0 mL (28.70 mmol) of triethylamine.The cold bath was removed and the reaction allowed to warm to roomtemperature and maintained for 30 minutes. The reaction was diluted withethyl acetate and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reducedpressure, and column chromatography of the residue on silica gel with 5%methanol/dichloromethane afforded 2.27 g of a light brown solid whichwas further purified via preparative HPLC to give 350 mg (14.4%) of thetitle compound. FAB MS [M+H]m/z; Calcd: 608, Found: 608.

[0586] The intermediate 4-[1-benzyl-3-(R)-benzylpiperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl/acetamidewas prepared as follows:

[0587] a. 1-Benzyl-3-(R)-benzylpiperazine-2,5-dione-4-t-butyl acetate.

[0588] To a solution containing 7.0 g (23.78 mmol) of1-benzyl-3-(R)-benzyl piperazine-2,5-dione described by Steele, et al.(J. Biorg, Med. Chem. Lett., 5:47 (1995)) in 125 mL of DMF under anitrogen atmosphere was added 5.30 mL (35.89 mmol) of t-butylbromoacetate and 6.80 g (29.34 mmol) of silver oxide. The reaction washeated to 50° C. overnight, diluted with ethyl acetate and washed withwater. The organic phase was dried over magnesium sulfate. Filtration,removal of solvent under reduced pressure and column chromatography ofthe residue on silica gel with 50% ethyl acetate/hexane afforded 7.74 g(79.7%) of the title compound as a white solid. FAB MS[M+H]m/z;Calcd:409,Found::409.

[0589] b. 1-Benzyl-3-(R)-benzyl-4-carboxymethylene-piperazine-2,5-dione.

[0590] To a solution containing 7.70 g (18.85 mmol) of1-Benzyl-3-(R)-benzyl piperazine-2,5-dione-4-t-butyl acetate in 300 mLof dichoromethane under a nitrogen atmosphere at 0° C. was added 19.0mL(191.30 mmol) of trifluroacetic acid. The reaction was allowed to warmto room temperature overnight. The solvent was removed under reducedpressure and the residue dissolved in ethyl acetate and washed withwater. The organic phase was dried over magnesium sulfate. Filtrationand removal of solvent under reduced pressure afforded 6.69 g ofproduct. FAB MS[M+H]m/z; Calcd:353,Found:353.

[0591] c.4-[1-Benzyl-3(R)-benzylpiperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide.

[0592] To a solution containing 2.0 g (5.68 mmol) of1-Benzyl-3-(R)-benzyl-4-carboxymethylene-piperazine-2,5-dione in 100 mLof dichloromethane and 2 mL of DMF under a nitrogen atmosphere at 0° C.was added 2.0 g (7.86 mmol) of BOPCI and 1.50 mL (8.62 mmol) of DIEA.After stirring for 30 minutes, a solution containing 1.80 g (5.7 mmol)of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 10 mL of dichloromethane and 4.0 mL (22.99 mmol) ofDIEA. The reaction was allowed to stir at 0° C. overnight, diluted withdichloromethane and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue on silica gel with 7% methanol/dichloromethane afforded 2.69 g (77.7%) of product. FAB MS[M+H]m/z;

[0593] Calcd:610, Found: 610.

Example 61

[0594] (CE-2128)4-[1-Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:608, Found: 608.

Example 62

[0595] (CE-2146)4-[1-Benzyl-3-(R)-benzylpiperazine-2,5,-dione]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:662, Found:662.

Example 63

[0596] (CE-2129)4-[1-Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:662, Found:662.

Example 64

[0597] (CE-2133)4-[1-Benzyl-3-(S)-benzylpiperazine-2,5,-dione]-N-[1-(3-[5-(2-dimethylaminoethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:575, Found:575.

Example 65

[0598] (CE-2084)4-[-Methyl-3-(R,S)-phenylpiperazine-2,5,-dione]-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:572, Found:572.

Example 66

[0599] (CE-2106)4-[1-Methyl-3-(R,S)-phenylpiperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:518, Found: 518.

Example 67

[0600] (CE-2162) 4-[1-(2-N-Morpholino ethyl)-3-(R)-benzylpiperazine-2,5,-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 59. FAB MS[M+H]m/z;Calcd:631, Found: 631.

Example 68

[0601] (CE-2149)5-(R,S)-Phenyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0602] To a mixture containing 0.28 g (2.10 mmol) of N-chlorosuccinimidein 50 mL of anhydrous toluene under a nitrogen atmosphere at 0° C. wasadded 0.23 mL (3.13 mmol) of dimethyl sulfide. The reaction was cooledto −25° C. using a carbon tetrachloride/dry ice bath, followed by theaddition of a solution containing 0.26 g (0.52 mmol) of5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-(2-[5(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 10 mL of toluene. The reaction was allowed to stir at −25° C. for 2hours, followed by the addition of 0.30 mL (2.15 mmol) of triethylamine.The cold bath was removed and the reaction allowed to warm to roomtemperature and maintained for 30 minutes. The reaction was diluted withethyl acetate and washed with water. The organic phase was dried overmagnesium sulfate. Filtration, removal of solvent under reduced pressureand column chromatography of the residue of silica gel with 10%methanol/dichloromethane, followed by preparative HPLC gave 120 mg(47.2%) of the title compound. FAB MS[M+H]m/z; Calcd:490, Found: 490.

[0603] The intermediate5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-(2-[5(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidewas prepared as follows:

[0604] a. (R)-N-(Ethoxy carbonylmethyl)-N′-(1-methoxycarbonyl-2-phenyl)urea.

[0605] To a solution containing 18.45 g (91.49 mmol) of(R)-2-phenylglycine methylester in 250 mL of ethyl acetate and 13.4 mL(96.12 mmol) of triethylamine under a nitrogen atmosphere at 0° C. wasadded 10 mL (91.49 mmol) of ethyl isocyanatoacetate. After stirring for1 h, the reaction was diluted with ethyl acetate and washed with water.The organic phase was dried over magnesium sulfate. Filtration andremoval of solvent under reduced pressure afforded 29.28 g (97.6%) ofproduct as a white solid. FAB MS[M+H]m/z; Calcd: 235, Found: 235.

[0606] b. (R)-5-Phenyl-3-carboxymethyl Hydantoin.

[0607] A mixture containing 29.28 g (99.49 mmol) of (R)-N-(ethoxycarbonylmethyl)-N′-(1-methoxy carbonyl-2-phenyl)urea in 500 mL ofconcentrated hydrochloric acid was heated to reflux overnight. Thereaction mixture was cooled to room temperature and extracted with ethylacetate. The organic phase was dried over magnesium sulfate. Filtrationand removal of solvent under reduced pressure afforded 14.01 g (60%) ofthe title compound. FAB MS [M+H] m/z; Calcd: 295, Found: 295.

[0608] c. 5-(R,S)-phenyl-2,4-imidazolidinedione-N-[1-(2-[5(3-methylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide

[0609] To a solution containing 2.55 g (10.89 mmol)of(R)-5-phenyl-3-carboxymethyl hydantoin in 100 mL of dichloromethaneand 10 mL of DMF under a nitrogen atmosphere at 0° C. was added 2.30 g(12.00 mmol) of EDCI and 1.62 g (11.99 mmol) of HOBT. After stirring 30minutes, a solution containing 4.43 g (14.21 mmol) of1-[2-(5-[3-methylbenzyl])-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-olhydrochloride in 20 mL of dichloromethane and 4.78 mL (43.50 mmol) ofNMM. The reaction was allowed to warm to room temperature overnight,diluted with dichloromethane and washed with water. The organic phasewas dried over magnesium sulfate. Filtration, removal of solvent underreduced pressure and column chromatography of the residue on silica gelwith 50% acetone/dichloromethane afforded 1.90 g (35.5%) of the titlecompound. FAB MS [M+H] m/z; Calcd: 490, Found: 490.

Example 69

[0610] (CE-2154)5-(S)-Benzyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 504, Found: 504.

Example 70

[0611] (CE-2142)5-(R)-Benzyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 504, Found: 504.

Example 71

[0612] (CE-2141)5-(R)-Benzyl-2,4-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 558, Found:558.

Example 72

[0613] (CE-2155)5-(S)-Benzyl-2,4-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 558, Found:558.

Example 73

[0614] (CE-2151)1-Benzyl-4-(R)-benzyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 594, Found: 594.

Example 74

[0615] (CE-2150)1-Benzyl-4-(R)-benzyl-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifluoromethylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.Prepared in a similar manner as shown in Example 67. FAB MS [M+H] m/z;Calcd: 648, Found:648.

Example 75

[0616] (ONO-PO-698)2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0617] To a mixture containing 410 mg (0.744 mmol, 77% purity) ofDess-Martin Reagent(1,1,1-triacetoxy-1,1-dihydro-1,2,benziodoxol-3-(1H)-one) in 4 mL ofdichloromethane was added dropwise a solution containing 410 mg (0.676mmol) of2-[5-benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidein 5 mL of dichloromethane. The reaction mixture was allowed to stir for1 hour. The reaction was quenched by addition of water, extracted withethyl acetate (×2). The extract was washed with water and a saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using aelution of 33% ethyl acetate/hexane to afford 372 mg of the tittlecompound. APCI, Pos, 40V [M+H] m/z; Calcd: 605, Found: 605.

[0618] The intermediate2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamidewas prepared as follows: to a solution containing 265 mg (1.01 mmol) of[1-[5-tert-butyl-1,3,4-oxadiazol-2-yl]-2-(S)-amino-1-hydroxy-3-methylbutanehydrochloride and 336 mg (0.843 mmol) of5-[(Benzyloxycarbonyl)amino]-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]aceticacid (J. Med. Chem., 38:98-108 (1995)) in 2 mL of anhydrous DMF wasadded 155 mg (1.01 mmol) of HOBT and 231 mg (1.01 mmol) of EDC1. Themixture was cooled to 0° C. and 0.11 mL (1.0 mmol) of NMM was addeddropwise and the reaction mixture was allowed to stir for 3 hours. Thereaction was quenched by addition of water and extracted with ethylacetate (×3). The extract was washed with aqueous 10% citric acidsolution, a saturated sodium hydrogencarbonate solution and a saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using agradient elution of 0 to 1% methanol/chloroform to afford 418 mg of thetittle compound. APCI, Pos, 40V [M+H] m/z; Calcd: 607, Found: 607.

Example 76

[0619] (ONO-PO-690)2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 667, Found: 667.

Example 77

[0620] (ONO-PO-697)2-[5-(Benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. El, Pos, [M+H] m/z;Calcd: 624, Found: 624.

Example 78

[0621] (ONO-PO-716)2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Neg, 40V [M−H]m/z; Calcd: 454, Found: 454.

Example 79

[0622] (ONO-PO-722)2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Neg, 40V [M−H]m/z; Calcd: 516, Found: 516.

Example 80

[0623] (ONO-PO-727)2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 456, Found: 456.

Example 81

[0624] (ONO-PO-730)2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Neg, 40V [M−H]m/z; Calcd: 436, Found: 436.

Example 82

[0625] (ONO-PO-731)2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Neg, 40V [M−H]m/z; Calcd: 498, Found: 498.

Example 83

[0626] (ONO-PO-732)2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 438, Found: 438.

Example 84

[0627] (ONO-PO-734) 2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 454, Found: 454.

Example 85

[0628] (ONO-PO-735)2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 436, Found:436.

Example 86

[0629] (ONO-PO-737)2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamidewas prepared in a similar manner to Example 75. APCI, Pos, 40V [M+H]m/z; Calcd: 438, Found:438.

Example 87

[0630] (ONO-PO-696) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.

[0631] To a mixture containing 296 mg (0.49 mmol) of2-[5-(benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamideand 0.32 mL (2.9 mmol) of anisole in 8 mL of dichloromethane at OEC wasadded dropwise a solution containing 392 mg (2.9 mmol) of aluminumchloride in 4 mL of nitromethane. The reaction mixture was allowed tostir for 1.5 hours, quenched by addition of ice water, extracted withethyl acetate (×3). The extract was washed with water and a saturatedsodium chloride solution. The organic phase was dried over anhydrousmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using aelution of 66% ethyl acetate/hexane to afford 175 mg of the tittlecompound as a white solid. APCI, Pos, 40V [M+H] m/z; Calcd: 471, Found:471.

Example 88

[0632] (ONO-PO-691)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos, [M+H] m/z;Calcd: 533, Found: 533.

Example 89

[0633] (ONO-PO-692)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos, [M+H] m/z;Calcd: 547, Found: 547.

Example 90

[0634] (ONO-PO-693) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos, [M+H] m/z;Calcd: 519, Found: 519.

Example 91

[0635] (ONO-PO-694) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl)acetamidewas prepared in a similar manner to Example 91. AP CI, Pos, 40V [M+H]m/z; Calcd: 491, Found:491.

Example 92

[0636] (ONO-PO-695)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-pyridyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. AP CI, Pos, 40V [M+H]m/z; Calcd: 492, Found: 492.

Example 93

[0637] (ONO-PO-699)2-[5-Amino-6-oxo-2-4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(4-methoxyphenyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide was prepared in a similar manner to Example 91.FAB, Pos [M+H] m/z; Calcd: 521, Found: 521.

Example 94

[0638] (ONO-PO-701)2-[5-Amino-6-oxo,-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl)-3,4-dihydroxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 565, Found: 565.

Example 95

[0639] (ONO-PO-703)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-benzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 505, Found:505.

Example 96

[0640] (ONO-PO-704)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-methyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos [M+H] m/z;Calcd: 429, Found:429.

Example 97

[0641] (ONO-PO-705)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-isopropyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 457, Found: 457.

Example 98

[0642] (ONO-PO-706)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos [M+H] m/z;Calcd: 471, Found: 471.

Example 99

[0643] (ONO-PO-707)2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos [M+H] m/z;Calcd: 453, Found: 453.

Example 100

[0644] (ONO-PO-711)2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-α,α-dimethybenzyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. FAB, Pos [M+H] m/z;Calcd: 515, Found: 515.

Example 101

[0645] (ONO-PO-712)2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd:454, Found:454.

Example 102

[0646] (ONO-PO-714) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-l-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 469, Found: 469.

Example 103

[0647] (ONO-PO-715)2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 516, Found: 516.

Example 104

[0648] (ONO-PO-7 18) 2-[5-Amino-6-oxo-2-(4-fluorophenyl)1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 47 1, Found: 471.

Example 105

[0649] (ONO-PO-72 1)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd: 533, Found:533.

Example 106

[0650] (ONO-PO-728)2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Neg, 40V [M−H]m/z; Calcd:449, Found:559.

Example 107

[0651] (ONO-PO-729)2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamidewas prepared in a similar manner to Example 91. APCI, Pos, 40V [M+H]m/z; Calcd:453, Found:453.

Example 108

[0652] (ONO-PO-733)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamidewas prepared in a similar manner to Example 9 1. APCI, Pos, 40V [M+H]m/z; Calcd:471, Found:471.

Example 109

[0653] (ONO-PO-736)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamidewas prepared in a similar manner to Example 9 1. APCI, Pos, 40V [M+H]m/z; Calcd:453, Found:453.

Example 110

[0654] (ONO-PO-700)2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0655] To a mixture containing 66 mg (0.093 mmol) of2-[5-(benzyloxycarbonyl)amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide(the compound prepared in a similar manner to Example 75) was added 2.5mL of 30% hydrobromic acid in acetic acid solution. The reaction mixturewas allowed to stir for 1 hour, quenched by addition of ice water,extracted with ethyl acetate (×3). The extract was washed with water(×2) and a saturated sodium chloride solution. The organic phase wasdried over anhyudrous sodium sulfate, filtered and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel using a gradient elution of 0 to 1% methanol/chloroform toafford 41 mg of the title compound. El, Pos, [M+] m/z; Calcd:576,Found:576.

Example 111

[0656] (ONO-PO-702)2-[5-(Methylsulfonyl)amino-6-oxo-2-(4-fluorphenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide

[0657] To a mixture containing 187 mg (0.36 mmol) of2-[5-amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide(the compound prepared in Example 25) in 3.5 mL of pyridine at OEC underan atmosphere of argon was added 0.028 mL (0.36 mmol) of mesyl chloride.The reaction mixture was allowed to stir -for 17 hours at roomtemperature, 15 hours at 50EC and 1 hour at 70EC. The reaction mixturewas quenched by addition of ice water, extracted with dichloromethane.The extract was washed with a saturated sodium chloride solution. Theorganic phase was dried over anhydrous sodium sulfate, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using a gradient elution of 50 to 66% ethylacetate/hexane to afford 60 mg of the tittle compound. APCI, Pos, 40V[M+H] m/z; Calcd: 597, Found:597.

Example 112 In Vitro Inhibition of Elastase

[0658] The following protocol was used to determine inhibitory activityof ONO-PO series of compounds. The elastase used in the protocol wasderived from human sputum (HSE). A mother solution of the HSE enzyme wasprepared from commercially available HSE (875 U/mg protein, SE-563,Elastin Product Co., Inc., Missouri, USA) by diluting with saline to1,000 U/ml, which was further diluted to 2 U/ml at 0° C. prior to use.

[0659] A solution was prepared by mixing 100 μl 0.2 M HEPES —NaOH buffer(pH 8.0), 40 μl 2.5 M NaCl, 20 μl 1% polyethyleneglycol 6000, 8 μldistilled water, 10 μl of a DMSO solution of inhibitor and 2 μl solutionof N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroaniline (at concentrationsof 100, 200 and 400 μM). The solution was incubated for 10 minutes at37° C. To this was added an enzyme solution of HSE (elastase derivedfrom human sputum). The resulting mixture was subjected to the followingrate assay.

[0660] Optical density (SPECTRA MAX 250, Molecular Devices) at 405 nmdue to p-nitroaniline generated by the enzyme reaction was measured at37° C. in order to measure the reaction rate during the period that theproduction rate of p-nitroaniline remains linear. The rate, mO.D./min.,was measured for 10 minutes at 30 second intervals immediately after theaddition of the enzyme solution. IC₅₀ values were determined bylog-logit method and converted to K_(i) values by Dixson plot method.The values are presented in Table 2 below. TABLE 2 Ki K_(i) Compound(nM) Compound K_(i) (nM) Compound (nM) ONO-PO-690 78.3 ONO-PO-710 2.39ONO-PO-730 23.5 ONO-PO-691 0.52 ONO-PO-711 2.55 ONO-PO-731 4.02ONO-PO-692 1.37 ONO-PO-712 16.6 ONO-PO-732 62.2 ONO-PO-693 2.71ONO-PO-713 12 ONO-PO-733 11.8 ONO-PO-694 24.8 ONO-PO-714 15.3 ONO-PO-73443.8 ONO-PO-695 13.9 ONO-PO-715 3.54 ONO-PO-735 26.4 ONO-PO-696 6.38ONO-PO-716 44.3 ONO-PO-736 6.43 ONO-PO-697 27.3 ONO-PO-717 57.8ONO-PO-737 36.3 ONO-PO-698 0.77 ONO-PO-718 26.2 ONO-PO-699 21.2ONO-PO-719 836.3 ONO-PO-700 1.18 ONO-PO-720 25.9 ONO-PO-701 2.98ONO-PO-721 13.5 ONO-PO-702 1.78 ONO-PO-722 3.35 ONO-PO-703 2.25ONO-PO-723 163.1 ONO-PO-704 14.0 ONO-PO-724 14.4 ONO-PO-705 10.7ONO-PO-725 4281.4 ONO-PO-706 6.76 ONO-PO-726 589.5 ONO-PO-707 3.59ONO-PO-727 132.8 ONO-PO-708 729.9 ONO-PO-728 8.75 ONO-PO-709 25.7ONO-PO-729 29.1

[0661] CE compounds were tested as described in WO 96/16080. Results arepresented in Table 2 below. As shown, the compounds of the invention arepotent inhibitors of elastase, with certain compounds showingsubnanomolar levels of inhibitory activity.

Example 113 Blood Level Screening

[0662] The inhibitors were dissolved or suspended in polyethylene glycol(PEG), PEG-400 or PEG:H₂O:EtOH at a concentration of 10 mg/ml. Unfastedmale Sprague-Dawley rats were given an oral dose of this solution bygavage. Rats received 10 mg inhibitor/kg body weight in a volume of 1ml/kg. After 1, 3 or 6 hr., the rats were killed with an overdose ofurethane (2.5 g/kg; i.p.) and the blood collected in a heparinized tubevia cardiac puncture. Red blood cells were separated from the plasma bycentrifugation.

[0663] Depending on the inhibitor, one of four organics (ethyl acetate,toluene, isopropyl ether or methyl t-butyl ether) was used to extractthe compound from the plasma. Inhibitor concentrations were measured byHPLC or LC/MS analysis. The results are presented in Table 2 below.Certain compounds of the invention demonstrate high levels of oralbioavailability as shown by their blood level concentrations over time.

Example 114 Extracellular Matrix (ECM) Assay Procedure

[0664] Forty-eight well plates on which extracellular matrix had beenestablished were supplied to Cortech by Dr. Simon's group at the StateUniversity of New York at Stony Brook. Briefly, the plates were preparedas follows: R22 rat heart smooth muscle cells were seeded into wells at2.5×10⁴ cells/cm. The cells were fed every 4 days with Eagle's MinimalEssential Media supplemented with fetal bovine serum, tryptose phosphatebroth, cefotaxime and streptomycin. At confluence, daily supplements of50 ug/ml ascorbic acid were added for 8 to 10 days during the synthesisof the ECM layer. [³⁵S]sulfate and [³H]proline were also added to theculture media to incorporate radiolabel into the matrix. Cells werelater lysed with 25mM NH₄OH. Plates were washed three times with waterand once with phosphate-buffered saline containing 0.02% NaN₃. Plateswere stored at 4° C. until use.

[0665] Matrix degradation assays were performed as follows: 0.40 ml ofHanks balance salt solution (HBSS) containing 1 or 5 uM test inhibitor(final concentration; diluted from DMSO stock solution; <2% DMSO finalconcentration) was added to the wells. After 30 minutes, 50 ul of apolymorphoneucleocyte (PMN) suspension was added resulting in 5×10⁵cells/well. PMN's were stimulated with opsonized zymosan. Zymosanparticles were washed and suspended in 0.5 ml human serum for 1 hr at37° C., vortexing every 15 min. The particles were then washed threetimes with HBSS and added to wells at a ratio of 10 particles/PMN in avolume of 50 ul. After a 4 hr incubation at 37° C., a 100 ul aliquot ofthe supernatant was withdrawn for scintillation counting. Followingremoval of the remaining supernatant, the residual ECM was solubilizedwith 0.5 ml 2M NaOH. The amount of tritium in this solubilized ECM wasaccessed by scintillation. ECM degradation data are expressed as(soluble counts released/total ECM counts)−(basal counts releasedwithout PMN's/total ECM counts). The results are presented in Table 3below. TABLE 3 HNE K_(i) ECM DATA % Inhibition Plasma Levels (μM) CE#(nM) 1 uM 5 uM 1 hr 3 hr 6 hr CE2048 0.2 CE2049 0.5 CE2050 1.84 CE20511.56 CE2052 0.37 CE2053 0.41 CE2054 0.29 CE2055 0.49 0.002 CE2056 0.98CE2057 0.375 CE2058 0.564 CE2061 71600 CE2062 0.3 CE2064 0.44 CE20650.47 CE2066 0.98 CE2067 3.6 CE2068 800 CE2069 4.4 CE2072 0.025 64.874.55 0.277 0.115 0.061 CE2073 0.235 CE2074 1 CE2075 0.039 CE2076 1.5CE2077 0.15 CE2078 1.05 CE2079 34 CE2080 62 CE2082 53 CE2083 73 CE2084133 CE2087 20 CE2088 66 0.801 0.755 CE2089 1.5 CE2090 2.7 CE2091 270CE2092 6.3 CE2093 0.26 CE2094 10 CE2095 0.21 60.43 55.63 CE2096 0.79CE2097 115 CE2098 85 CE2099 1.9 0.042 CE2100 0.069 57.63 56.56 0.064CE2101 0.64 44.582 51.18 1.238 1.369 1.042 CE2102 258 CE2103 12.4 CE21040.33 CE2105 0.72 CE2106 41 CE2107 17 CE2108 10.5 CE2109 126 CE2110 0.13CE2111 20 0.69 CE2112 1.2 CE2113 39 1.835 0.909 CE2114 25 CE2115 1CE2116 76 CE2117 586 CE2118 13.2 CE2119 7.7 CE2120 51 CE2121 28 CE212263 CE2123 15 CE2124 0.033 CE2125 0.4 0.011 CE2126 5 0.161 CE2127 34CE2128 64 CE2129 300 CE2130 2.1 16.32 29.02 0.162 CE2131 265 CE2132 23.5CE2133 33000 CE2134 2 21.71 25.724 5.02 CE2135 17.5 0 37 CE2136 104CE2137 558 CE2138 294 CE2139 41 CE2140 204 CE2141 64 CE2142 8.7 CE214311.5 CE2144 9.3 CE2145 0.038 CE2146 67 CE2147 1600 CE2149 0.28 51.27555.9 0 0 0 CE2151 59 14.25 −8.3 CE2152 0.24 CE2154 10 54.6 65.4 CE215557 CE2156 512 CE2157 1.4 9.96 13.42 3.81 CE2159 52 CE2160 260 CE21610.082 25 55 CE2162 10.6 0.025 CE2163 0.75 54.7 64 0.316 CE2164 17 0.034CE2165 2.6 0.067 CE2166 145 CE2168 0.15 CE2170 297 CE2171 0.64 CE21722.2 0.021 CE2173 6.5 35.9 47.1 CE2174 15.2 1.49 18.3 1.86 0.97 CE2176 52CE2177 0.016 74.2 76.78 0.393 0.41 0 CE2178 0.29 34 0.185 CE2179 7.648.8 45.9 1.229 0.599 CE2180 44 CE2181 46 CE2182 54 CE2183 0.23 CE21848.2 30.5 32.4 0.57 CE2185 0.27 CE2186 0.037 CE2187 42 CE2189 99 CE219029 CE2191 85 29.35 30.5 CE2192 7.3 40.8 49.7 CE2193 36 CE2194 2.4 4158.7 1.11 0.553 CE2195 10.6 CE2196 96 CE2197 4.8 CE2198 3.1 CE2200 13.7CE2202 0.12 CE2203 79 0.004 CE2204 7.4 0.48 CE2205 37 0.475 CE2206 8.747.4 62.3 CE2207 1.2 0 CE2208 40 CE2209 36.4 0 CE2210 22.7 CE2211 348CE2212 124 CE2213 0.14 0.19 CE2214 0.92 0 CE2215 163 1.16 0.83 0.63CE2216 4.1 32.1 37.15 0.77 0.47 0.25 CE2217 5.5 28.1 41.2 1.99 0.521CE2218 1.6 30.5 33.15 CE2219 537 CE2220 52 CE2221 34 CE2223 0.93 34.1536.15 CE2224 1 43.25 66.8 1.843 1.943 1.961 CE2225 8.2 30.85 43.45CE2226 10.3 27.55 52.25 CE2227 40 1.276 0.74 0.962 CE2228 40 0.714 1.3930.409 CE2229 9.5 31.25 48.2 CE2230 2.6 37.7 37.8 0 CE2231 16 1.226 0.7870.531 CE2232 0.15 0.44 0.44 0.26 CE2233 41.6 54.7 55.4 0.07 0.065 0.036CE2234 796 39.7 35 CE2235 9.5 19.75 13.25 CE2236 7.1 31.9 31.75 CE2237 334.6 42.6 1.02 1.8 0.84 CE2238 162 10.1 18.8 2.573 1.739 1.028 CE2239 4311.9 11.3 1.46 1.15 0.71 CE2240 30 16.8 13.5 1.12 0.5 0.29 CE2241 1418.6 31.7 0.598 0.289 0.078 CE2242 27 29.4 40.7 CE2243 11 48 54.9 2.8012.104 1.598 CE2244 78.5 CE2245 24 34.7 39.3 CE2246 18.5 −2.3 32.6 1.1820.837 0.496 CE2247 62.4 13.3 21.2 1.017 0.572 0.186 CE2248 3.1 39.4 63.21.65 1.58 1.22 CE2249 13 22.4 42.4 1.179 0.704 0.213 CE2250 6.9 27.448.6 CE2251 0.43 54.1 74.5 1.63 1.11 0.73 CE2252 1.9 45.4 65.2 0.1140.188 0.1 CE2253 11 31.9 45.9 0.282 0.246 0.163 CE2254 2.4 57.2 58.41.751 1.575 2.316 CE2255 18 20.7 42 CE2256 16 24 47.8 0.9 0.33 0.2CE2257 30 48.3 61.4 CE2258 3.7 42.9 38.1 1.624 1.5 1.212 CE2259 3.3 4359.6 0.597 0.846 0.502 CE2260 0.39 68.3 59.7 3.532 3.053 1.894 CE22610.36 CE2262 0.42 CE2263 0.67

Example 115 Ex Vivo Inhibition of Elastase

[0666] Sixty (60) minutes after the oral administration of an inhibitorwith an appropriate vehicle, a blood sample (0.9 ml) is collectedthrough the abdominal aorta by a syringe containing 0.1 ml of a 3 .8%sodium citrate solution.

[0667] The blood sample is processed as follows: 60 μl of (final 0.1-1mg/ml) a suspended solution of opsonized zymosan in Hank's buffer isadded to the preincubated whole blood (540 μl) for 5 minutes at 37° C.,and the resulting mixture is incubated for 30 minutes at the sametemperature. The reaction is terminated by immersing the test tube intoice water. The reaction mixture is then centrifuged at 3,000 rpm for 10minutes at 4° C. Twenty (20) μl each of the resulting supernatant (theSample) is measured for elastase activity.

[0668] The mixture consisting of the following components is incubatedfor 24 hours at 37° C., and then optical density is measured at 405 nm:0.2 M tris-HCl buffer (pH 8.0) 100 μl 2.5 M NaCl  40 μl Distilled water 36 μl 50 mM solution of a substrate(*)  4 μl The Sample  20 μl

[0669] A test sample mixed with 1-methyl-2-pyrrolidone instead of thesubstrate is regarded as Substrate (−). A test sample mixed with salineinstead of the Sample is regarded as Blank. The remaining elastaseactivity in the Sample is calculated according to the following:

[0670] optical density of Substrate (+)−(optical density of Substrate(−)+optical density of Blank)

[0671] as a total production of p-nitroaniline over 24 hours based on astandard curve for the amount of p-nitroaniline.

[0672] An average activity is calculated based on the test sample of 5-6animals. An agent at 3, 10 or 30 mg/kg is orally given by a forcedadministration to a 24 hour fasted animal at 60 minutes before the bloodsampling. Optical density is measured by SPECTRA MAX 250 (MolecularDevices).

We claim:
 1. A compound of the formula:

wherein R₁ is alkyl; or R₁ is a cyclic moiety selected from the groupconsisting of phenyl, cyclopropyl, and benzyl, which cyclic moiety isoptionally substituted with one or more of the following: alkyl oralkylenedioxy; R₂ and R₃ are hydrogen or isopropyl; R′₂ and R′₃ arehydrogen; R₁₃ is hydrogen or fluoro; X is N; Y is O; V₁ and V₃ are C; V₂is N or C; V₄ is N; and R₁₄—A is amino or hydrogen; wherein the compoundis selected from the group consisting of:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(3-pyridyl)-1, 6-dihydro-1-pyrimidinyl]-N-1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-1-(2-[5-tert-butyl-1,3,4-oxadiazolyl)carbonyl]-2(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-methyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-isopropyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide;2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide;2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide;and2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropylacetamide.
 2. The compound of claim 1, wherein R₁ is methylcyclopropyl,and the compound is selected from the group consisting of:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;and2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.3. The compound of claim 2:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.4. The compound of claim 2:2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.5. The compound of claim 2:2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.6. The compound of claim 2:2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.7. The compound of claim 1, wherein V₂ is N, and the compound isselected from the group consisting of:2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;and2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.8. The compound of claim 7:2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.9. The compound of claim 7:2-[5-Amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.10. The compound of claim 1, wherein R₁ is benzyl optionally substitutedby alkyl, and the compound is selected from the group consisting of:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;and2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.11. The compound of claim 10:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[l-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.12. The compound of claim 10:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
 13. The compound of claim 10:2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.14. The compound of claim 10:2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.15. The compound of claim 1, wherein R₁ is alkyl, and the compound isselected from the group consisting of:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl)carbonyl]-2(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-methyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-isopropyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide;2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide;2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide;2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide;2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide;and2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide.16. The compound of claim 15:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl)carbonyl]-2(S)-methylpropyl]acetamide.17. The compound of claim 15:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-methyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.18. The compound of claim 15:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-isopropyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.19. The compound of claim 15:2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.20. The compound of claim 15:2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pylimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.21. The compound of claim 15:2-[6-Oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide.22. The compound of claim 15:2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide.23. The compound of claim 15:2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.24. The compound of claim 15:2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide.25. The compound of claim 15:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.
 26. The compound of claim 15:2-[5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.27. The compound of claim 15:2-[6-Oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]acetamide.28. The compound of claim 15:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]acetamide.29. The compound of claim 1:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.
 30. The compound of claim 1:2-[5-Amino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetamide.